full-length review eye fields in the frontal lobes of primates

Ž .Brain Research Reviews 32 2000 413–448www.elsevier.comrlocaterbres

Full-length review

Eye fields in the frontal lobes of primates

Edward J. Tehovnik), Marc A. Sommer, I-Han Chou, Warren M. Slocum, Peter H. SchillerDepartment of Brain and CognitiÕe Sciences, Massachusetts Institute of Technology, E25-634, Cambridge, MA 02139, USA

Accepted 19 October 1999

Abstract

Two eye fields have been identified in the frontal lobes of primates: one is situated dorsomedially within the frontal cortex and will beŽ .referred to as the eye field within the dorsomedial frontal cortex DMFC ; the other resides dorsolaterally within the frontal cortex and is

Ž .commonly referred to as the frontal eye field FEF . This review documents the similarities and differences between these eye fields.Although the DMFC and FEF are both active during the execution of saccadic and smooth pursuit eye movements, the FEF is morededicated to these functions. Lesions of DMFC minimally affect the production of most types of saccadic eye movements and have noeffect on the execution of smooth pursuit eye movements. In contrast, lesions of the FEF produce deficits in generating saccades to brieflypresented targets, in the production of saccades to two or more sequentially presented targets, in the selection of simultaneously presentedtargets, and in the execution of smooth pursuit eye movements. For the most part, these deficits are prevalent in both monkeys andhumans. Single-unit recording experiments have shown that the DMFC contains neurons that mediate both limb and eye movements,whereas the FEF seems to be involved in the execution of eye movements only. Imaging experiments conducted on humans havecorroborated these findings. A feature that distinguishes the DMFC from the FEF is that the DMFC contains a somatotopic map with eyesrepresented rostrally and hindlimbs represented caudally; the FEF has no such topography. Furthermore, experiments have revealed that

Ž .the DMFC tends to contain a craniotopic i.e., head-centered code for the execution of saccadic eye movements, whereas the FEFŽ .contains a retinotopic i.e., eye-centered code for the elicitation of saccades. Imaging and unit recording data suggest that the DMFC is

more involved in the learning of new tasks than is the FEF. Also with continued training on behavioural tasks the responsivity of theDMFC tends to drop. Accordingly, the DMFC is more involved in learning operations whereas the FEF is more specialized for theexecution of saccadic and smooth pursuit eye movements. q 2000 Elsevier Science B.V. All rights reserved.

Keywords: Dorsomedial frontal cortex; Supplementary eye field; Frontal eye field; Oculomotor behaviour; Skeletomotor behaviour; Learning; Monkey;Human

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414

2. The anatomy of the DMFC and the FEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4162.1. The anatomy of the DMFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4162.2. The anatomy of the FEF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4192.3. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420

3. Electrical stimulation of the DMFC and the FEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4203.1. Maps and coding schemes in monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4203.2. Electrical stimulation and the behavioural state of monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4213.3. Skeletomotor responses elicited by electrical stimulation of the DMFC and FEF in monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . 4233.4. DMFC and FEF stimulation in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4233.5. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

4. Lesions and reversible inactivation of the DMFC and the FEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4234.1. The effects of lesions and reversible inactivation of the DMFC in monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4234.2. The effects of lesions and reversible inactivation of the FEF in monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4244.3. Direct comparison of DMFC and FEF lesions and inactivation on visually guided eye movements . . . . . . . . . . . . . . . . . . . . . . . 426

) Corresponding author. Fax: q1-617-253-8943; e-mail: [email protected]

0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.Ž .PII: S0165-0173 99 00092-2

( )E.J. TehoÕnik et al.rBrain Research ReÕiews 32 2000 413–448414

4.4. The effects of DMFC and FEF damage in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4274.5. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428

5. Single-cell recordings in the DMFC and FEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4295.1. The characteristics of single neurons in the DMFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4295.2. The characteristics of single neurons in the FEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4305.3. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431

6. Event-related potentials in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

7. Metabolic imaging of the DMFC and FEF in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435

8. Motor learning and the DMFC and FEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

9. Misplaced human FEF? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437

10. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439

Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

1. Introduction

Two areas within the frontal lobes play important rolesin eye movement control. One area resides laterally and is

Ž .known as the frontal eye field FEF . The other residesmedially and dorsally and is often termed the supplemen-

Ž w x.tary eye field see Schall 230 . As will become clear fromthis review, the size, exact location, and precise function ofthis second eye field are still under debate; therefore, werefer to it using the anatomical designation, the dorsome-

Ž .dial frontal cortex DMFC , or more specifically ‘‘the eyefield within the DMFC’’. Our examination of the literaturesuggests that the differences between the two frontal lobeeye fields, the FEF and DMFC, are profound. The FEFplays an important role in generating eye movements,utilizing an eye-centered code, whereas the DMFC inte-grates oculomotor and skeletomotor behaviour, utilizingpredominantly a head-centered code, and is involved invisuo-motor learning.

One of the first investigators to examine the role of thew xcortex in eye-movement control was Hitzig 106 . Studying

patients unable to move their eyes voluntarily, Hitzigfound that he could induce eye movements by deliveringpulses of direct current through electrodes attached to theskull. Hitzig believed that the eye movements producedwere due to excitation of brain tissue. However, the result-ing eye movements could have been due to surface con-duction to the eye muscles; to resolve this ambiguity,Hitzig needed to stimulate the brain directly. In collabora-tion with Fritsch, he performed these experiments on dogs.In 1870 they established that neocortical stimulation elicitedmovement of the extremities, but they failed to produce

w xeye movements 68,307 .

w xSoon thereafter, Ferrier 59 discovered that eye move-ments could be evoked in monkeys from parts of thefrontal, parietal, and temporal lobes, the superior colliculi,and the cerebellum. The frontal lobe eye field that Ferrierdescribed extends from the arcuate sulcus to the midlineŽ .Fig. 1A,B . It is remarkable that the only major modifica-tion to this eye field since Ferrier’s original publication hasbeen a split into two subfields, one wholly within the curveof the arcuate sulcus and the other about a centimeteraway, near the midline.

At the end of the 19th century, tissue removal andelectrical stimulation were the main techniques used toexamine brain function in animals. Interpretation of theformer was difficult due to qualitative, irreproducible be-

w xhavioural testing and post-operative infections 77,107 .Electrical stimulation results, on the other hand, were more

w xunequivocal and enlightening. Beevor and Horsley 10confirmed Ferrier’s findings showing that eye movementscould be elicited from both the prearcuate gyrus and theperi-midline cortex in the frontal lobe of monkeys. Theyfurther showed that eye movements could be evoked from

w xthe lateral frontal convexity of an ape as well 11 , and thisw xwas confirmed by Grunbaum and Sherrington 92 and¨

w xLeyton and Sherrington 144 after the turn of the centuryin orangutans, chimpanzees, and gorillas. However, neitherof these groups uncovered the existence of an eye fieldnear the midline of their apes. Subsequently, investigatorsfocused on the prearcuate eye field, which eventuallybecame known as the FEF; the medial eye field representa-tion was essentially ignored for decades.

Neurosurgeons were, in large part, responsible for re-viving scientific curiosity about the eye fields in the

w xDMFC. Foerster 60,61 reported that there were two main

( )E.J. TehoÕnik et al.rBrain Research ReÕiews 32 2000 413–448 415

Ž .Fig. 1. Classic results in examining the neocortical contribution to eye movements. Anterior is to the left and dorsal to the top unless otherwise noted. Aw x ŽStimulation regions of Ferrier 59 , lateral view. In the frontal lobe, eye movements were evoked from region 12 only border surrounding it is emphasized

. w x Ž .in bold . Species was Macaca cynomolgus, according to Walker 302 , although this was not noted in Ferrier’s paper. B Dorsal view of Ferrier’sŽ . Ž . w xstimulation regions anterior at top . C Foerster’s map of movements and sensations evoked by electrical stimulation of human brain 60 . The two frontal

lobe eye fields he found are outlined in bold. Note, in an apparent attempt to simplify his presentation, he superimposed his functional findings on thew xcytoarchitectural map of Vogt and Vogt 296 . Human brain landmarks relevant to this review are labeled: IFS, inferior frontal sulcus; MFG, middle frontal

Ž . Ž .gyrus; SFS, superior frontal sulcus; PCS, precentral sulcus; CS, central sulcus also known as Rolandic sulcus . D Map of human peri-Rolandic motorw xand sensory areas, from Penfield and Jasper 194 .

regions from which eye movements could be evoked in thehuman frontal lobe. One was in the FEF, on the lateral

Žconvexity of the cortex lower bold-outlined region in Fig..1C , and the other was in Vogts’ area 6ab, medial to the

Ž .FEF upper bold-outlined region in Fig. 1C . Both regionswere anterior to the primary, precentral motor strip. Foer-

w xster 60 did not specify what part of Area 6ab was relatedw xto eye movements. Penfield and Jasper 194 and Penfield


w xand Rasmussen 195 clarified the location of the 6ab eyefield in their subsequent studies of the human brain, local-izing it to the rostral part of the supplementary motor areaŽ .Fig. 1D . Penfield also confirmed Foerster’s finding thatthe human FEF was on the lateral convexity, anterior to

Ž .the precentral motor strip Fig. 1D, lower set of eyes . Atw xabout the same time, Woolsey 309 and Woolsey et al.

w x311 showed in an assortment of animals that the repre-sentation of the body was oriented eyes-rostrally and tail-caudally in the DMFC of every animal studied.

Since the 1950s, research directed toward the neuralcontrol of eye movements has profited from five major

Ž .methodological advances: 1 the development of a varietyof microelectrodes suitable for single-cell recordings and

Ž .for microstimulation; 2 the emergence of instrumentationthat allowed investigators to accurately measure eye move-

Ž .ments; 3 the introduction of behavioral methods thatmade it possible to train animals to move their eyes inresponse to sensory stimuli in predictable, reproducible

Ž .ways; 4 the development of techniques that allowed formaking focal brain lesions or for reversibly inactivatingselected brain areas using a variety of pharmacological

Ž .agents; and 5 the application of various imaging proce-dures to localize areas involved in eye-movement control.This review focuses extensively on research conductedusing these methods. We will compare and contrast thefunction and organization of the two eye fields in thefrontal lobes based on research carried out in primates,including humans.

2. The anatomy of the DMFC and the FEF

2.1. The anatomy of the DMFC

2.1.1. Monkey DMFCIn monkeys, the DMFC is situated anterior to the motor

cortex. It occupies a region between the superior limb ofthe arcuate sulcus and the cerebral midline dorsal to the

w xcingulate cortex. Brodmann 29 defined this area as themesial portion of area 6. Subsequently, this region was

w xpartitioned. Vogt and Vogt 295 divided the DMFC intoŽrostral and caudal zones: 6ab and 6aa , respectively Fig.

. w x2A . von Bonin and Bailey 297 also partitioned theDMFC into rostral and caudal zones, but the rostral zone

w xwas appreciably smaller. Barbas and Pandya 8 dividedthe DMFC into three regions, a medial region they calledMII, a rostrolateral region they called 6DR, and a caudalregion they called 6DC. Some have also suggested that the

w xDMFC includes area 8b 147 , which is situated immedi-w xately adjacent to the anterior border of area 6 20 .

w xWoolsey et al. 311 observed that the DMFC contains asomatotopic map with the head represented rostrally andthe tail represented caudally. Although some have disputed

w xthis general topography 305 , there is now overwhelmingevidence corroborating the original observations of

w xWoolsey 27,64,66,86,110,149,166,228,243,275,308 .Single-unit recording experiments have shown that neu-

rons modulated by eye movements are located rostrally,that neurons modulated by hindleg movements are located

Ž .Fig. 2. Monkey DMFC. Each panel shows a top view of one hemisphere of the frontal cortex of a macaque monkey. A The DMFC is divided accordingw x Ž .to the scheme of Vogt and Vogt 295 . B Each oval represents a region from the DMFC that contained cells modulated by eye, forelimb, and hindlegŽ w x . Ž .movements in the same monkey Brinkman and Porter 27 , monkey SMA-3 . C Each oval represents a region from the DMFC from which movements

Ž w x . Ž .could be evoked using electrical stimulation Luppino et al. 149 , monkey MK-7r . D The DMFC is divided according to the scheme of Matelli et al.w x Ž . Ž . Ž . Ž .159 . A scale bar is shown at the bottom. The central sulcus Cs , arcuate sulcus As , and principal sulcus Ps are indicated in A .


caudally, and that neurons modulated by forelimb move-ment are located in between the rostral and caudal ex-

Ž w x .tremes of the DMFC Ref. 27 ; see Fig. 2B . Neurons withresponses modulated by distal forelimb movement arefound anterior to those modulated by proximal forelimbmovements. These findings concur with results obtained

Ž w x .using microstimulation Refs. 149,166 ; see Fig. 2C .

2.1.2. Multiple sub-areas of monkey DMFCw xBased on cytoarchitectonics, Matelli et al. 159 parti-

tioned the DMFC into four regions: F2, F3, F6, and F7Ž .Fig. 2D . More recently, these regions have been givenfunctional labels now adopted by Tanji and colleaguesunder the premise that these regions are functionally dis-

w xtinct 69,161,162,173,254,255,277,279 . These labels havealso been used to organize data from functional imaging

w xexperiments carried out on humans 204 . In this nomen-clature, F2 corresponds with the premotor area, F3 withthe supplementary motor area, F6 with the pre-supplemen-tary motor area, and F7 with the supplementary eye fields.

The subdivisions, F2, F3, F6, and F7, as established byw xMatelli et al. 159 , were based on six macaque monkeys.

As sections were taken more rostrally in the DMFC,proceeding from F3 to F6 or from F2 to F7, the cells inlayer V exhibited a noticeable decrease in size. 1 Layer Vwas thicker in F3 than in F6 and layer V was thicker in F2than in F7. Progressing from caudal to rostral regions ofF3, a decrease in the frequency of the giant pyramidal cells

w xwas observed. Although Matelli et al. 159 suggest that F2differs from F3 and that F6 differs from F7, this is notapparent from their figures. 2 Based on their illustrations,one would be hard put to establish a difference between F2and F3 and a difference between F6 and F7. Furthermore,a discrete border between F3 and F6 and between F2 andF7 is hard to discern in their Fig. 3, which depicts horizon-tal sections including F3 and F6, and in their Fig. 7 whichdepicts parasagittal sections including F2 and F7. Currentanatomical techniques do not convincingly denote markeddifferences between these areas other than cell size andlaminar thickness.

Even though the cytoarchitectonics of the DMFC do notw xsupport the subdivisions of Matelli et al. 159 , the projec-

tions from these regions might favor a segregation suchŽthat eye-movement areas only innervate F7 the supple-

.mentary eye fields . The FEF and superior colliculus arew xconnected with area F7 5,67,108,132,231,257 , yet they

ware also connected with areas F2, F3 and F6 5,128,x132,231,257 .

Studies examining the projections between the DMFCŽand motor cortex show that the entire DMFC i.e., F2, F3,

.F6, and F7 sends projections to the forelimb area of the

1 w xMatelli et al. 159 : their Fig. 6, cf. F3 and F6 and their Fig. 9, cf. F2and F7.

2 w xCompare Fig. 5 with Fig. 8 of Matelli et al. 159 .

w xmotor cortex 56,79,129,140,146,160 . Motor cortex, how-w xever, does not project to F6 and F7 150 , although it does

w xinnervate F2 and F3 140,150 . Thus the cytoarchitectonicsand the efferent and the afferent connections of the DMFCdo not provide an unambiguous way of subdividing the

w xDMFC according to the scheme of Matelli et al. 159 .

2.1.3. Neuron size and somatotopy of monkey DMFCw xMatelli et al. 159 observed that the thickness of cortex

decreases from caudal to rostral DMFC. 3 The number ofcells within a cylinder of constant cross-sectional area of 1

2 w xmm of cerebral cortex is constant 16,23,217 , whichmakes it understandable why cortical thickness from cau-dal to rostral portions of the DMFC decreases concurrentlywith decreases in cell size as illustrated by Matelli et al.w x w x159 . Mitz and Wise 166 show that the number of cells

Ž 2 .with large diameters over 600 mm also decreases sys-tematically from caudal to rostral DMFC.

It is well-known that there is a direct correspondencew xbetween cell size and axon diameter 259 and that the

larger the cell, the further the axon tends to project fromw xthe cell body 114,172 . That cells decrease in size going

from caudal to rostral DMFC concurs with the somatotopyof the DMFC. Caudal DMFC, which has been associatedwith the hindlimbs, projects as far as the lumbarrthoracic

w xcord 99,110 ; intermediate DMFC, which has been associ-ated with forelimbs, projects as far as the cervical cordw x56,99,110,123,132,151,221 ; and rostral DMFC, whichhas been associated with the eyes and head, projects as far

w xas the brainstem 108,132,142,187,256,257 . Hence, thedifference in cell size across the DMFC accords with itsgeneral somatotopy.

2.1.4. ConnectiÕity of monkey DMFCAs already alluded by the foregoing, the DMFC is

innervated by both oculomotor as well as skeletomotorregions of the brain. It innervates the FEF and the superior

w xcolliculus 5,67,108,128,132,231,257 , both of which aremajor channels to the saccade generator in the brainstem.Also, it receives robust efferent and afferent projections

w xfrom the motor cortex 56,79,129,140,146,150,160 andwsends fibres to a myriad of brainstem 108,132,142,187,

x w x256,257 and spinal cord 56,99,110,123,132,151,221 nu-clei involved in the execution of eye, head, and limbmovements.

In addition, visual centers, such as the lateral intrapari-etal area and the medial superior temporal area, innervate

w xthe DMFC 108,232 , and somatosensory areas, such as thesuperior parietal lobule, send robust projections to itw x113,202 . Moreover, DMFC is reciprocally connected to

w xprefrontal cortex 108 and innervates various thalamic andstriatal sites that have been implicated in oculomotor and

3 Caudal: F2 and F3s2162 and 2157 mm, respectively. Rostral: F6and F7s1990 and 1992 mm, respectively.


Ž .Fig. 3. Monkey FEF. Anterior is to the right for panels A and C, and to the left for panel B. A Location of the FEF on a lateral view of monkey frontalŽ w x.lobe, defined using the -50 mA current-threshold criterion modified from Bruce et al. 31 . Small arrows and shading delimit the mediolateral range of

Ž .FEF. Most of the FEF, however, extends into the arcuate sulcus and cannot be seen. CS, central sulcus; AS, arcuate sulcus. B Monkey cortex asw x Ž w x . Ž .parcellated by Brodmann 29 . Species is presumably Cercopithecus campbelli see von Bonin and Bailey 297 , p. 64 . C Parcellation of prefrontal

w x Ž .cortex by Walker 301 . Species is M. mulatta. D Coronal section through the genu of the arcuate sulcus, showing the parcellation of von Bonin andw x Ž . Ž .Bailey 297 from mediodorsal top to ventrolateral right . Species is M. mulatta; as, superior branch of arcuate sulcus; ai, inferior branch of arcuate.

w xskeletomotor functions 108,125,128,158,187,258 . Finally,this region sends projections to the red nucleusw x108,257,289 .

2.1.5. Human DMFCAs in monkeys, the DMFC in humans is located imme-

diately anterior to the motor cortex on the dorsal surface ofŽ .the hemisphere Fig. 1C,D . The area is situated anterior to

the precentral sulcus and is bounded laterally by thesuperior frontal sulcus and medioventrally by the cingulate

w x w xcortex 32 . Brodmann 28 has defined this region asw xmesial area 6 of the agranular cortex and Campbell 32

called it the intermediate precentral area. Vogt and Vogtw x295 subsequently divided the region into caudal and

Ž .rostral zones i.e., 6aa and 6ab similar to what they haddone in the monkey. Electrical stimulation of this region inhumans evokes eye movements from rostral sites and

w xhindleg movements from caudal sites 194,310 . This topo-graphic layout is similar to that observed for the DMFC ofmonkeys.


2.2. The anatomy of the FEF

2.2.1. Monkey FEFThere has been general agreement among electrophysio-

logical studies regarding the gross location of the FEF inw xthe monkey. Ferrier 59 showed that electrical stimulation

of the prearcuate gyrus causes contraversive eye move-Ž .ments Fig. 1A . This central observation has been repeat-

w xedly confirmed 262 . The subsequent use of microelec-trodes facilitated the establishment of the exact location

w xand extent of the FEF. Bruce and Goldberg 30 function-ally defined the FEF as the region from which saccadiceye movements can be evoked with currents of less than50 mA. This region lies within the rostral bank of theposterior curve of the arcuate, extending anteriorly overthe lip of the arcuate ‘‘ . . . a few millimeters onto the

Ž w x .surface of the prearcuate gyrus’’ Ref. 31 , p. 723 , andposteriorly encroaching a few millimeters into the caudal

w xbank 84,85,248 . Mediolaterally, it extends about 10 mm,centered approximately on the arcuate’s midpoint as de-fined by the intersection of the straight extension of the

Ž .principal sulcus with the arcuate Fig. 3A . The overallarea of the FEF, approximately 100 mm2, is about equal tothe area of the DMFC.

The functionally defined FEF does not correspond toany of the classical cytoarchitectural regions defined by

w xanatomists of the 20th century. Brodmann’s area 8 29 isŽ .close with respect to its medial and lateral extent Fig. 3B ,

but is situated too far rostrally, extending anteriorly to thecaudal tip of the principal sulcus and posteriorly only to

Žthe lip of the arcuate sulcus as described by Walkerw x.301 . The functional FEF therefore overlaps with both

Ž .areas 8 and 6 of Brodmann. Walker’s area 8A Fig. 3Cextends 1r2 to 2r3 of the way down from the lip of thearcuate and hence, like Brodmann’s area 8, also fails tocover the full caudal extent of the FEF. Laterally, Walkerpicked out another region in the arcuate’s rostral bank and

Ž .called it area 45 Fig. 3C , but how far this extends intothe sulcus was not specified. Thus, in terms of Walker’snomenclature, the functional FEF overlaps with areas 8A

Ž .and 45 and encroaches caudally into Brodmann’s area 6 .w xvon Bonin and Bailey 297 included the medial half of the

Ž .arcuate’s rostral bank in their frontal granular region FD ,but they agreed with Walker that the lateral part differed

Žand called it FD gamma after the notation of von Economow x .and Koskinas 299 ; Fig. 3D . Other investigators have

split the cortex comprising the FEF into even more sub-w xfields, upon which we will not elaborate 203,211,295 .

Although the functionally defined FEF does not coin-cide neatly with traditionally defined cytoarchitectonic re-gions, it does have a distinct, constant anatomical feature.

w xStanton et al. 267 reported that the functionally definedFEF coincides with a relatively high concentration of largelayer V pyramidal cells in the arcuate’s rostral bank. This

w xfeature is so prominent that Stanton et al. 267 claimed itto be macroscopically evident in tangential sections through

the prearcuate gyrus. The layer V pyramidal cells arethought to be the major conveyors of oculomotor signalsfrom the FEF to the superior colliculus and the ponsw x247,248,267 .

Does any anatomical characteristic of tissue changesystematically across the FEF? Successive generations ofanatomists have disagreed about which microstructuralchanges in the FEF are reliable and important. The follow-ing changes are worth noting because they have beenindependently confirmed by the majority of anatomists; 4

how they relate to function, however, is unknown. FromŽ . Žrostral FEF near the arcuate lip to caudal near the

.fundus , a moderately thick and granular layer IV tapersoff, becoming almost invisible at the fundus and into theposterior bank, while radial fascicles become thicker. Frommedial FEF to lateral, layer III pyramidal cells get biggerand the distinct radial and horizontal myelination patternsthat exist in medial FEF become more diffuse.

w xThe FEF makes profuse reciprocal connections 109with the lateral intraparietal area, with area 46, with thecontralateral FEF, and with the eye field in the DMFC.Subcortically, the FEF is reciprocally and heavily con-nected with the lateral sector of the mediodorsal nucleus ofthe thalamus and, to a lesser extent, with thalamic regions

w xlateral and anterior to this 76,268 . The FEF projectsdirectly to the superior colliculus and to brainstem regions

w xfundamental to saccade generation 141 , and the FEFreceives reciprocal input from the superior colliculus via a

w xdisynaptic pathway relayed by the thalamus 153 . Thew xFEF also projects to the striatum 187,268 ; this projection

may be reciprocated through a polysynaptic loop to sub-stantia nigra pars reticulata, thalamus, and back to FEFw x3,153 .

2.2.2. Human FEFThe anatomy of human FEF is an enigma. The most

recent conclusions about the gross location of human FEFcome from experiments using positron emission tomogra-

Ž .phy PET imaging or functional magnetic resonanceŽ .imaging fMRI , and from these studies, it appears that the

w xhuman FEF lies within the precentral sulcus 43,148,189just caudal to the middle frontal gyrus. The human FEFseems to be placed surprisingly far back in the frontallobe; it is within, or attached to, the precentral motor strip.In monkeys, by contrast, the FEF is distinctly rostral to theprecentral motor strip. The human and monkey FEF aredissimilar in terms of their microstructures, as well. Inmonkeys, as already noted, a striking characteristic of theFEF is that, within it, layer IV changes rostrocaudally frombeing thick and granular to being nearly non-existent. Inhumans, however, the FEF lies entirely in agranular cortexŽ .Fig. 4A . The major thalamic input to monkey FEF is the

4 To our knowledge, modern myelin staining has been performed inw xthe FEF by only one laboratory 211 . Therefore, our myelination conclu-

sions are based on a single report and one might consider them tentative.


Fig. 4. Human FEF. Anterior is to the left and dorsal is to the top.Ellipses show the approximate locations of human FEF as determined by

Ž .imaging studies. A Basic cytoarchitecture of human frontal lobe. Region2 is the extent of granular frontal cortex; caudal to that, region 1, in

Žwhite, is agranular frontal cortex the granularity of regions caudal to theŽ . .central sulcus CS is not considered . Imaging studies place the human

Ž .FEF in the precentral sulcus PCS , totally in agranular cortex. Derivedw xfrom Walker 301 , who based his figure on the human brain study of von

w x Ž .Economo and Koskinas 299 . B Connections of the human brain withrespect to thalamus. The ‘‘regio frontalis’’ is connected primarily with

Ž .the mediodorsal MD nucleus of the thalamus; the region caudal to thatŽ .is connected primarily with the ventrolateral VL thalamic nucleus.

w xModified from Bailey and von Bonin 7 .

mediodorsal nucleus, as noted above. In humans, the gen-eral layout of thalamic projections to the cortex has been

w xestimated 7 by analyzing retrograde degeneration subse-w xquent to prefrontal leucotomy or lobectomy 65,165 and

w xby extrapolating results from monkeys 300 . According tothis mapping, it is doubtful that the human FEF receives

Ž .substantial mediodorsal thalamus input Fig. 4B . Rather,like its neighbor, the precentral motor strip, the humanFEF appears to receive its primary afferents from moreventrolaterally located nuclei.

The human FEF, as determined by imaging methods,therefore, is strikingly different from the monkey FEF.Imaging investigators recognize this conflict and have

w xoffered a number of explanations for it 43,148,189 . Wewill return to this topic later in the review.

2.3. Summary

Two distinct areas involved in eye-movement controlhave been discerned in the frontal lobe, the FEF and theeye fields in the DMFC. In the monkey, the FEF is locatedin a well-defined region of the arcuate sulcus. The FEFreceives extensive projections from area 46, the intrapari-etal sulcus, the DMFC, and the contralateral FEF; layer Vcells in the FEF project extensively to subcortical centersincluding the superior colliculus and the brainstem.

The exact size and location of the eye field in theDMFC are not as clearly defined as in the FEF. However,it is evident that the size of cells increases antero-posteri-orly in the DMFC and that the projections from theanterior regions terminate mostly in the brainstem whilethose from the posterior regions have projections thatreach the spinal cord. The DMFC innervates regions thatmediate both oculomotor and skeletomotor responses.

The two eye fields have also been identified in thehuman. The FEF in the human is located more closely tothe central sulcus than it is in the monkey. The inputs tothese areas and their outputs are less well-known in hu-mans than in monkeys.

3. Electrical stimulation of the DMFC and the FEF

3.1. Maps and coding schemes in monkeys

w xIn 1969, Robinson and Fuchs 216 showed that electri-cal stimulation of the FEF elicited fixed-vector saccadiceye movements such that the size and direction of theelicited saccades were largely invariant with the initialposition of the eyes in orbit. They also noted an orderlyarrangement of stimulation-elicited saccades in the FEFŽwhich was first alluded to by the work of Beevor and

w x.Horsley 10 : in the ventrolateral regions, small-amplitudesaccades were evoked, whereas stimulation of the dorso-

Ž .medial regions yielded large-amplitude saccades Fig. 5A .w xRobinson and Fuchs 216 also found that when long trains

of stimulation were delivered to the FEF, a staircase ofsaccades was elicited with alternating saccades and fixa-

Žtions, so that each saccade had a similar vector Fig. 5B,. w xright . Bruce et al. 31 confirmed the FEF’s map of

saccadic amplitudes, and also found that the direction ofsaccades varied as a function of the depth of stimulation inthe arcuate sulcus. Numerous other studies have confirmed

w xthese basic findings 6,80,157,229,233,282,284 .Electrical stimulation of the DMFC yields notably dif-

ferent results from those obtained in the FEF. It has beenw xknown since 1987 243 that saccades evoked by electrical

stimulation from most sites within the DMFC tend to shiftthe center of gaze to a particular location of craniotopic


Ž .Fig. 5. Coding schemes. A Cranio- and retinocentric coding schemesdescribed for the DMFC and FEF, respectively, are shown. A side-viewof the macaque monkey brain is depicted. Each box represents the visualspace in front of a monkey with head fixed. The right side of a boxrepresents contralateral craniotopic space and the left side represents

Ž .ipsilateral craniotopic space i.e., with respect to the side of stimulation .The arrows within each box represent saccades starting from differentfixation positions. The top boxes show the types of saccades evoked fromsites situated along the rostrocaudal axis of the DMFC. A shaded circlerepresents the termination zone of the saccades evoked from a given site.The boxes aligned at left show the types of saccades evoked from sites

Ž .situated along the mediolateral axis of the FEF. B Horizontal eye tracesare shown of saccades evoked from the DMFC and FEF. Below each eyetrace is a black bar which represents the onset and duration of electrical

Ž .stimulation. Top When a 400-ms train of stimulation was delivered tothe DMFC, a single saccadic eye movement was evoked and when such atrain of stimulation was delivered to the FEF, a series of saccadic eye

Ž .movements was evoked. Bottom When a 70-ms train of stimulation wasdelivered to the DMFC or FEF, a single saccadic eye movement wasevoked.

space. This finding has been confirmed by the presentw xauthors laboratory 139,156,264,282,283,285,286 as well

w xas by others 19,229 . The orbital position reached by theeye upon stimulation has subsequently been named the

w xtermination zone 282 . The location of a termination zonecorresponds to the location of the fixation fields of neurons

w xin the stimulated area 19 . Further work revealed that theDMFC contains an orderly topographic map representing

w xdifferent termination zones 139,264,282,283,285,286 :stimulation of rostral sites in the DMFC elicits saccadesthat shift the direction of gaze into contralateral cran-iotopic space, whereas stimulation of caudal sites shifts

Žgaze into central or ipsilateral craniotopic space Fig. 5Aw x.139 ; stimulation of medial and lateral sites direct theeyes to lower and upper craniotopic space, respectively.When the head is displaced with respect to the trunk or

when the head is tilted with respect to the vertical axis, thelocation of a termination zone remains fixed to the headw x285 . When long trains of stimulation are delivered to theDMFC, only one saccadic eye movement is typically

Ž . w xproduced Fig. 5B, left 229,243,282,284 after which theeyes remain fixated in the termination zone for the dura-tion of stimulation, thereby inhibiting any subsequent eye

w xmovements 282,283 . These results suggest that theŽDMFC, unlike the FEF, contains a craniocentric or head-

.centered code for the execution of saccadic eye move-ments.

In conflict with these reports is a study by Russo andw xBruce 222 who found that stimulation in the DMFC

produces saccadic eye movements similar to those foundin the FEF: the size and direction of the saccadic eyemovements did not vary remarkably with respect to thestarting position of the eye. There could be several reasonsfor this difference. First, it is possible that area DMFC isnot homogeneous; different subregions may carry differentcodes. Second, it is possible that stimulation at certain sitesin the DMFC antidromically activated axon collateralsfrom the FEF. Consistent with this hypothesis, our experi-

Ž w x .ence has been Ref. 264 and unpublished observationsthat fixed vectors can be evoked from the DMFC at about

Ž .4% of sites Ns53 penetration , but only within narrowlydefined depths; stimulation a few hundred microns aboveor below these sites again yields craniocentric saccades.Ablation or inactivation of the FEF during stimulation ofthe DMFC could test the hypothesis that fixed-vectorsaccades elicited from the DMFC occur by virtue ofactivating the collaterals of FEF neurons. The third possi-ble reason that Russo and Bruce obtained what look likefixed-vector saccades is that they used only short-durationstimulation trains of 70 ms. Under such conditions, thesaccades elicited from the DMFC often do not reach their

w xfull extent 284 . An example of this is shown in Fig. 6,demonstrating that the amplitude of stimulation-elicitedsaccades increases with increasing train duration. In theexperiments of Russo and Bruce, low current levels wereused which may have also contributed to the execution oftruncated saccades. This, however, cannot be the entireexplanation since others have managed to evoke conver-gent saccades from the DMFC using low currentsw x19,229,243 . For more details regarding these issues, see

w x w xSchall 230 and Tehovnik 280,281 .

3.2. Electrical stimulation and the behaÕioural state ofmonkeys

It has been shown in many experiments that the proba-bility of evoking a saccadic eye movement with electricalbrain stimulation is influenced by the behavioral state ofan animal. Such factors as state of alertness and intent tofixate or to carry out a specific task can significantly alterthe size, direction, or latency of saccadic eye movementsor affect the current threshold at which saccades are


Fig. 6. Effect of train duration on saccades evoked from the DMFC. Theleft hemifield, out to 108, is shown for a monkey. The animal fixated atarget located in central craniotopic space. Electrical stimulation wasdelivered to one site in the DMFC to evoke saccades contralateral to theside of stimulation. The arrows point to the end points of the elicitedsaccades when using stimulation trains of 120, 160, and 200 ms. Noticethat the amplitude of the saccades increased systematically with increasesin train duration.

w xproduced 19,69,82,131,157,186,237,253,266 . A recentexamination of the effectiveness of stimulation in thefrontal lobes has shown that the behavioural state ofanimals has a much greater effect on saccadic eye move-ments evoked electrically from the DMFC than from the

w xFEF 284 . Monkeys were required to fixate a visual targetfor 600 ms after which a juice reward was given. Electricalstimulation was delivered at various times during and afterfixation. When stimulating the DMFC early during the

Ž .fixation period, 16 times as much current Fig. 7A wasrequired to evoke saccades than when current was deliv-

Ž .ered after termination of the fixation spot Fig. 7C . Whenthe same manipulations were carried out in the FEF, only

Ž .three times as much current Fig. 7B was required toevoke saccades early during fixation as compared with

Ž .stimulation after the fixation spot was turned off Fig. 7C .This finding for the FEF concurs with the results of

w xGoldberg et al. 82 . The probability of evoking saccadesfrom the DMFC was also noticeably decreased when theduration of active fixation was decreased or when thedelivery of juice reward was delayed; stimulation-elicitedsaccades from the FEF were much less affected by these

variables. These results, along with the finding that lowŽ . Žcurrents e.g. -50 mA , short train durations e.g., -70

. Ž .ms , and high pulse frequencies e.g., )300 Hz are moreeffective in evoking saccades from the FEF than from theDMFC, suggest that the FEF, compared to the DMFC, ismore closely connected to the saccade generator in the

w xbrainstem 284,286 .

Fig. 7. Current threshold for eliciting saccades on 70% of stimulationŽ .trials is plotted as a function of stimulation onset time for the A DMFC

Ž . Ž .and B FEF. Curves ‘‘a’’ through ‘‘f’’ in A represent the currentthresholds for evoking saccades from sites in the DMFC, and curves ‘‘a’’

Ž .through ‘‘h’’ in B represent the current thresholds for evoking saccadesfrom sites in the FEF. Stimulation was delivered 200 ms after the

Ž .termination of the fixation spot 200 ms , 0 ms after the termination ofŽ .the fixation spot 0 ms , 200 ms before the termination of the fixation

Ž .spot y200 ms , or 400 ms before the termination of the fixation spotŽ .y400 ms . The left panel shows the method. The top grey bar represents

Ž .the duration of fixation fix , which was 600 ms, and the black barsrepresent onset and duration of stimulation which was 200 ms. Juice wasdelivered immediately after the fixation spot was terminated as long asthe animal remained fixated for the 600 ms. No juice was delivered if theanimal broke fixation during this period, whether the break was self-ini-

Ž .tiated or stimulation-induced. C A normalized threshold ratio is plottedas a function of stimulation onset time for the DMFC and FEF. The ratiowas computed by dividing the mean current required to evoke saccades ata given stimulation onset time by the mean current required to evokesaccades at a stimulation onset time of 200 ms. Standard errors areindicated. Pulse duration and pulse frequency were 0.2 ms and 200 Hz,

w xrespectively. Data from Tehovnik et al. 284 .


3.3. Skeletomotor responses elicited by electrical stimula-tion of the DMFC and FEF in monkeys

As indicated earlier, the DMFC, within which the sup-plementary motor area resides, contains a topographic mapof the body. Stimulation of rostral sites tends to evoke eyemovements, whereas stimulation of caudal sites tends toevoke hindlimb movements; stimulation of intermediate

Ž .sites tends to evoke forelimb movements Fig. 2C . Otherresponses that have been evoked from the DMFC includeear and neck movements, as well as eyelid blinkingw x20,243 . In contrast, skeletomotor responses are not read-

w xily triggered from the FEF 31,157,216,233,237,239 .

3.4. DMFC and FEF stimulation in humans

It has been known for some time that electrical stimula-tion delivered to either the DMFC or the FEF in humans

w xevokes eye movements 60 . Such stimulation of the hu-man DMFC has disclosed a somatotopic map similar to

w xthat observed in the monkey 194,310 . These findingsw xhave recently been replicated 66,78 . Penfield and Welch

w x196 found that stimulation of some sites in the DMFCevoked a contralateral gaze shift that was accompanied byan arm movement coincident with the change in the direc-

Žtion of gaze represented by cartoon in supplementary.motor area of Fig. 1D . These findings suggest that the

DMFC may be involved in hand–eye coordination and thatforelimb and eye have a common termination position that

w xis laid out in a topographic fashion in this structure 282 .w xPenfield and Welch 196 also found that stimulation deliv-

ered to the DMFC often inhibited the execution of move-ments. These findings are in consonance with the alreadynoted finding that in the monkey, visually evoked saccadesare inhibited when the eyes are already positioned in the

w xtermination zone 282,283 .

3.5. Summary

Saccadic eye movements can be elicited with electricalstimulation from both the FEF and the DMFC. The natureof the saccadic eye movements produced, however, isquite different in the two areas.

In the FEF, the saccadic eye movements elicited haveconstant vectors; the amplitude and direction of a saccadeat each site stimulated are largely unaffected by initial eyeposition. Prolonged stimulation produces a staircase ofequal-size saccades. There is a clear topographic order inthe FEF, with large amplitude saccades represented inmedial portions and small amplitude saccades representedin lateral portions of the anterior bank of the arcuate.

In the eye fields of the DMFC, electrical stimulation atmost sites elicits saccadic eye movements that bring theeyes to a specific orbital position. Prolonged stimulationholds the eye in place at that position. There is a topo-graphic order in the DMFC eye field area representing

different terminal positions. At some sites in this region,one can also elicit eye movements with constant vectors.More posteriorly in the DMFC, electrical stimulation canproduce skeletomotor responses. Such responses are soma-totopically ordered.

In general, eye movements can be produced more reli-ably and with lower currents in the FEF than in theDMFC. This is especially true when an animal is activelyfixating.

4. Lesions and reversible inactivation of the DMFC andthe FEF

4.1. The effects of lesions and reÕersible inactiÕation of theDMFC in monkeys

Many groups have studied the effect of DMFC lesionsŽ won forelimb movement tasks e.g., Refs. 25,26,35,147,

x. w x188,227,255,288,306 . In 1984, Brinkman 26 made le-sions of various portions of the DMFC confined to the

Ž .mesial bank Fig. 8A . The animals were tested on twotasks. In the first, a unimanual task, monkeys were re-quired to remove small morsels of food embedded in slotscut into a board. The orientation of each slot was different,requiring the animal to orient his fingers appropriately toextract the food item. In the second task, a bimanual one,monkeys were required to use both hands to obtain thefood morsels. One hand was needed to push the food itemthrough a slot and the other to grab it. Shortly afterunilateral DMFC lesions, monkeys were impaired on bothof these tasks; they no longer adjusted the orientation oftheir hands to extract the food in the unimanual task. Bothhands showed impairment. On the unimanual task, thedeficit disappeared after 2 weeks. In contrast, the poorperformance on the bimanual task persisted even 1 yearafter the lesion.

w xLucchetti et al. 147 found that following a lesion ofŽ .the DMFC that included anterio-lateral regions Fig. 8B , a

monkey was impaired at reaching toward visual objectspresented in contralateral space. This deficit subsided after1 month, however.

w xIn another set of experiments, Thaler et al. 288 andw xChen et al. 35 made bilateral lesions of the DMFC that

included both the mesial and lateral regions of the areaŽ .Fig. 8C . Monkeys were trained on several tasks. In thefirst, they had to displace one lever at the onset of a visualstimulus and then displace another lever upon the termina-tion of the stimulus. In the second task, monkeys weretrained to delay the movement of a joystick by havingthem activate the joystick 5–8 s after the onset of a visualstimulus. In the third task, the animals had to shift thejoystick to the left and then forward after the visualstimulus appeared. In the fourth task, reversal learning wasassessed by making reward contingent on repeatedly press-ing the joystick to the left and then, after 27 trials, to the


w xFig. 8. DMFC lesions in monkeys. The method of Tehovnik 280 wasused to determine the size and location of DMFC lesions across variousstudies. The rostrocaudal and mediolateral extents of a lesion weredetermined in millimeters and the location of a lesion was determined

Ž .with respect to the cerebral midline Ml and posterior tip of the arcuateŽ .sulcus Pa . In each panel, the tick marks along the midline axis are

Ž .spaced by 1 mm. A The overlapped rectangles show the location of thew xchronic lesions of monkeys used in the study of Brinkman 26 : monkeys

Ž .SMX1, SMX2, M6, M7, M9. Lesions were all unilateral. B Therectangle shows the extent and location a chronic lesion of a monkey

w x Ž .used by Lucchetti et al. 147 . The lesion was unilateral. C Theoverlapped rectangles show the location of the chronic lesions of mon-

w x w xkeys used in the study of Thaler et al. 288 and Chen et al. 35 : monkeysŽ .62, 63, 64, 65, 66, 67, 83, 84, 85. Lesions were bilateral. D The shaded

rectangles represent the sites injected with muscimol in monkeys BT andw xPS of Shima and Tanji 255 . The dotted rectangle represents the maximal

spread of the muscimol which was estimated to be 2.0 mm from thew x Ž .cannula tip 255 . All injections were bilateral. E The rectangle repre-

sents the location and size of a cooling probe used in the study of Sasakiw x Ž .and Gemba 227 . Cooling probes were situated bilaterally. F The

shaded rectangles represent the sites injected with lidocaine in the studyw xof Sommer and Tehovnik 264 . The anterior-most rectangle represents

the injection sites of Monkey L and the posterior-most rectangle repre-sents the injection sites of Monkey I. The dotted rectangle represents themaximal spread of the lidocaine. Each injection was estimated to spread

w x Ž .1.5 mm from the cannula tip 287 . All injections were unilateral. G Therectangle shows the extent and location of a typical chronic lesion in the

w xstudy of Schiller and Chou 234 : monkey 3. Lesions were typicallyunilateral.

right; the number of trials required for successful reversalwas assessed. Damage to the DMFC had little effect on theperformance of these tasks. The last two tasks did show a

minor deficit, but continued training rapidly reinstatedpre-operative performance. One additional task was usedin which monkeys were required to break a photobeamwith their forelimbs in order to obtain a reward. Theanimals were exposed to this task for 30 minrday. On thistask, 3 weeks after a DMFC lesion, monkeys were still

Ždeficient. However, due to limited testing only four occa-.sions , these results are difficult to evaluate.

Using reversible inactivation methods, Shima and Tanjiw x255 showed that the learning of a sequential task, whichrequired animals to move a manipulandum to successive

Ž .positions by a push, pull, or turn , was disrupted whenmuscimol was injected bilaterally into various regions of

Ž .the DMFC Fig. 8D . The severity of the deficit decreasedwith the repetition of a particular sequence, however.When the monkeys were required to execute the move-ments in the presence of visual cues, no deficit wasobserved following inactivation.

In another reversible inactivation experiment in which alarge portion of the DMFC was cooled both unilaterally

Ž . w xand bilaterally Fig. 8E , Sasaki and Gemba 227 showedthat performance was disrupted on a task that required thelifting of a lever when a visual stimulus appeared. Theyfound that the latency with which the animals lifted thelever upon the appearance of the visual stimulus increasedwhen tissue was cooled. The effect, however, was transi-tory; after 2 months of continued testing, the responselatencies were no longer affected by cooling. When asimilar experiment was performed on the motor cortex, thedisruptive effect of cooling on lever lifting never fadedw x226 . Corroborating the amelioration of deficits with re-

w xpeated cooling is a study by Miyashita et al. 168 , whohave shown that after extensive training, inactivation of theDMFC becomes ineffective.

Only a few studies have examined the effects of DMFCinactivation and lesions on oculomotor responses. Sincethese studies compared directly the effects of DMFC andFEF lesions or inactivation, they will be considered in aseparate section below.

4.2. The effects of lesions and reÕersible inactiÕation of theFEF in monkeys

The effects of FEF ablations and inactivation have beenextensively studied. Investigators who have examined theexecution of saccadic eye movements to singly appearingstationary visual targets report that after FEF ablation orinactivation, the deficits are moderate. There is a smalldecrease in saccadic velocities and an increase in saccadiclatencies; this has been reported both with lesions and with

wreversible inactivation using lidocaine or muscimol 52,x54,234,238,240,263 . After FEF ablation, there is relatively

rapid recovery in both saccadic velocities and saccadiclatencies. Time for recovery is longer for saccades made tovisual targets appearing at relatively large eccentricitiesŽ . w x108–208 235,236 . Reversible inactivation studies also


show that monkeys have difficulty in acquiring targets thatappear beyond 158 of eccentricity from straight ahead and

w xto then maintain fixation on them 263 . This deficit has itscounterpart in the fact that there is a decrease in saccadicamplitude that is especially notable for large saccadesfollowing FEF ablations. These deficits recover at aboutthe same rate as does the deficit in saccadic latencyw x235,236 .

In contrast to the relatively mild and short-lastingdeficits in the latency and amplitude of saccades made tovisual targets and in maintained fixation, ablation or inacti-

Ž .vation of the FEF Figs. 9 and 10A,B,C,D dramaticallyaffects the execution of single saccades generated to re-

Ž .membered target positions. FEF lesions Fig. 10A,B,Ealso interfere with two successive saccades made in re-sponse to two successively presented targets. Deficits ingenerating such ‘‘memory-guided saccades’’ persist even 4

Ž .months after an FEF ablation Fig. 10C .Ž .The effects of FEF lesions Fig. 10F on the execution

of smooth pursuit eye movements elicited by movingtargets have also been examined. Deficits in pursuit have

w xbeen reported both with lesions and inactivation 152,251 .Pursuit deficits typically occur for targets moving in adirection ipsilateral to the side of the lesion. Deficits inpursuit are still apparent beyond 10 weeks after an FEF

w xablation 120 . To obtain clear deficits in visually guidedpursuit, the deeper portions of the arcuate, including thefundus and portions of the posterior bank, must be ablated

w xor inactivated 154 . The deficits in pursuit so obtained arew x Ž .in consonance with two related findings 84,85,154 : 1

there are neurons in the depth of arcuate sulcus, including

Ž .Fig. 9. Size and location of FEF lesions in monkeys. A The size andlocation of an FEF lesion were determined by noting the extent of a

Ž . Ž .lesion with respect to the superior As and inferior Ai limbs of thearcuate and with respect to an axis originating at the posterior tip of the

Ž . Ž .arcuate Pa and extending anteriorly toward the principle sulcus Ps .Ž . Ž .The anterior ant and posterior post portions of the arcuate sulcus are

also shown so that the depth of the lesion into each bank can be assessed.Ž .The shaded area is a hypothetical FEF lesion. B The length of each axis

Ž .Y, X, and Z was set to 1. For the hypothetical lesion shown in ‘‘A’’,the length of the Y vector is 0.7, the X vector is 0.6, and the Z vector is

Ž . Ž .0.4. C By joining the endpoints of each vector dotted line in B incombination with the borders of the lesion into the anterior and posteriorbank, the size and location of an FEF lesion are described.

Fig. 10. FEF lesions in monkeys. The size and location of FEF lesions areshown for various studies investigating oculomotor and skeletomotor

Ž .behaviour. The shaded area represents the lidocaine injection sites of AŽ . w xMonkey L and B Monkey I in Sommer and Tehovnik 263,264 . The

dotted area represents the maximal effective spread of lidocaine. Eachw xinjection was estimated to spread 1.5 mm from the cannula tip 287 . All

Ž .injections were unilateral. C The shaded area represents the extent ofw xthe chronic lesion in the monkey used by Deng et al. 52 . The lesion was

Ž .unilateral. D The shaded area represents the chronic lesion of a monkeyw x Ž .used by Funahashi et al. 70 : monkey YM. The lesion was unilateral. E

The shaded area represents a typical chronic lesion in the study ofw xSchiller and Chou 234 : monkey 3. The lesions were usually unilateral.

Ž .F The overlapped dotted regions show the location of chronic lesions ofw xmonkeys used in various studies: Keating 120 : monkeys Big1, Big2,

w x w xSML; Keating 121 : monkey S1, S2, S3; Keating et al. 122 : monkey 3;w x w x Ž .Lynch 152 : monkey R5; MacAvoy et al. 154 : monkey 420. G The

shaded area represents the chronic lesion of a monkey used by Schiller etw x Ž .al. 240 : monkey Bn. The lesion was bilateral. H The overlapped dotted

regions show the location of chronic lesions of monkeys used by van derw x Ž .Steen et al. 291 : monkeys F1, F2, F3. Lesions were unilateral. I The

overlapped dotted regions show the location of chronic lesions of mon-w xkeys used by Halsband and Passingham 95 : monkeys FEF33, FEF34.

Lesions were bilateral. For other details, see Fig. 9.

the fundus, that are modulated during smooth pursuit; andŽ .2 electrical stimulation of this region evokes smoothpursuit eye movements.

A number of studies have also investigated the effect ofFEF ablations on visually guided forelimb movementsw x w x46,95,214,240,291 . Schiller et al. 240 trained monkeysto pick apple pieces from slots imbedded in a board. Theslots in the board spanned 608=608 of visual space.

Ž .Immediately after a bilateral FEF lesion Fig. 10G , mon-keys were impaired at retrieving apple pieces from theboard; complete recovery was evident by the fourth post-

w xoperative week. van der Steen et al. 291 trained monkeysto press, within 1 s following its illumination, a buttonwhich was presented at one of 19 positions spaced at 58

intervals over a horizontal 908 arc in front of an animal.


Ž .Two days after a unilateral FEF lesion Fig. 10H , mon-keys failed to push the illuminated target that appearedanywhere contralateral to the side of the lesion. Thirty-fivedays after the lesion, monkeys were still impaired atcontralateral locations beyond 308. Monkeys had difficul-ties in making large gaze shifts which were compensatedby the animals making head movements of increasedamplitude.

In another set of experiments, Halsband and Passing-w xham 95 trained monkeys on a conditional motor task. The

animals had to push a sphere when a green light came onand a cube when the light turned orange. The position ofthe sphere and the cube was randomized. Following bilat-

Ž .eral lesions of the FEF Fig. 10I , monkeys did very poorlyand failed to relearn the task; they were exposed to 3500trials over a 3-month period. Unoperated controls masteredthe task within 1 month and 1200 trials.

4.3. Direct comparison of DMFC and FEF lesions andinactiÕation on Õisually guided eye moÕements

Only two sets of experiments have compared the effectson eye movements of lesions or reversible inactivation ofthe DMFC and FEF in monkeys. In the first set ofexperiments, the DMFC or FEF was reversibly inactivated

Ž w x.with lidocaine or muscimol Figs. 8F and 10A,B 263,264while monkeys performed various eye movements. Inacti-vation of the DMFC did not interfere with the ability tofixate visual targets in different parts of visual space or toexecute saccadic eye movements to single visual targets or

w xto remembered target locations 264 . However, inactiva-tion of the FEF, as already noted, had dramatic effects onthese tasks; the most pronounced deficits were obtainedunder conditions when animals had to make saccadic eye

w xmovements to remembered target locations 263 . Whenmonkeys were required to generate a sequence of twosaccades to two remembered targets, both DMFC and FEF

w xinactivation produced deficits 263,264 . Monkeys wereoften unable to generate saccades to either the first or the

second target. The magnitude of the impairment was muchgreater after FEF inactivation than it was after DMFCinactivation.

The second set of experiments compared eye-movementw xperformance after FEF and DMFC ablations 234 and

reported similar deficits to those found during reversibleinactivation. DMFC lesions produced a mild impairmentthat recovered within weeks on the execution of successivesaccadic eye movements made to sequentially presentedtargets. FEF lesions, on the other hand, produced a muchmore dramatic deficit on this task that lasted even after 2years of continued testing. The areas lesioned are depictedin Figs. 8G and 10E.

In addition to these tasks, the study comparing FEF andDMFC lesions used a test in which two identical targetswere presented, with one appearing in each hemifieldw x234 . Monkeys were rewarded for choosing either target.This task was similar to the one used in clinical studies

wthat explore the extinction phenomenon 46,124,147,214,x291,304 . In addition to having the targets appear simulta-

neously, they were also presented with various temporalonset asynchronies. This enabled the investigators to deter-mine how choice of the targets shifted as a function of thetemporal offset between them. In normal animals, theequal probability point at which the frequency of left andright target choices was similar occurred close to the timewhen they appeared simultaneously. However, after a uni-lateral DMFC or FEF lesion, a major shift arose in choicepreference. The temporal shift was much greater andlonger-lasting after an FEF lesion than after a DMFClesion. To get equal probability choices for the left andright targets, a temporal asynchrony of more than 110 mshad to be introduced 2 weeks after removal of the FEF,with the target in the hemifield contralateral to the lesionhaving to appear first. The temporal offset for equal proba-bility choice 2 weeks after a DMFC lesion was only 31ms. Recovery, after the DMFC lesion, was complete after4 months; after FEF lesions, even a year later, more than a60-ms offset was necessary for equal probability choice.Fig. 11 shows data on this task.

Fig. 11. Target selection. Data obtained from two monkeys are shown as obtained with paired targets presented with varied temporal asynchronies. Plottedis the percent of saccades made to the left target as a function of temporal offset between the paired targets. Data are shown at various times after recovery

Ž . Ž . Ž .from a left FEF LFEF or right DMFC RDMFC lesion as well as pre-operatively pre-op . Squares and solid lines depict data from the animal with theFEF lesion; circles and dotted lines depict data from the animal with the DMFC lesion. Records of saccadic eye movements made to paired targets with

Ž .various temporal offsets in the intact animal appear as an inset. For each of the post-operative weeks plotted wk2–wk16 , data were collected for five orw xsix successive days. Data from Schiller and Chou 234 .


One interpretation of these effects after unilateral abla-tion is that the lesions affect temporal discrimination dur-ing target selection. To test this, monkeys were trained to

w xdiscriminate temporal differences in target onset 234 ;they had to select the target in an array that came onvarious times prior to the other similar stimuli. The ani-mals were rewarded only for making a saccadic eye move-ment to the target that had appeared first. This task re-vealed major deficits in making temporal discriminationsafter FEF lesions and mild but significant deficits afterDMFC lesions. Thus, one major effect of FEF lesions, andto a lesser extent of DMFC lesions, is to impair temporaldiscrimination.

One animal in this study was also examined after boththe DMFC and the FEF had been removed. The deficitsafter such paired lesions were of about the same magnitude

w xas single lesions to the FEF 235,236 . These lesions didnot produce any deficits in smooth pursuit eye movements,probably because the FEF lesion did not include damage tothe fundus and posterior bank of the arcuate.

4.4. The effects of DMFC and FEF damage in humans

4.4.1. Deficits on oculomotor tasksEffects of frontal lobe damage on the oculomotor be-

Žhaviour of humans have been studied widely e.g., Refs.w x.24,73,74,93,100,170,190,205–207,213 . Unfortunately,the brain damage in such patients is usually not restrictedto the FEF or DMFC; it often includes damage to severalother regions. In considering the effects of damage to theDMFC and FEF, we focused on results obtained frompatients whose lesions did not extend well beyond either

Ž .the FEF or DMFC Fig. 12 . In the human, the FEF isgenerally considered to be in or near the precentral sulcusŽ w x.e.g., Ref. 189 and the DMFC straddles the midline withsignificant overlap into the mesial bank. Most of our FEFcases included damage to regions rostral to, but alsoincluding, the precentral sulcus. The findings may besummarized as follows.

Ž .1 Patients with lesions of either the FEF or DMFCcould generate saccades as well as normal subjects tovisual targets. The lesions are depicted in Fig. 13A.

Ž . Ž .2 Patients with a unilateral FEF lesion Fig. 13B, lefttrained to make saccades to remembered target positions in

Ž .total darkness typically a 2-s delay generated hypometricsaccades to targets appearing contralateral to the side ofthe lesion; saccade reaction times were much longer thanthose exhibited by normal subjects. In contrast, DMFC

Ž .patients Fig. 13B, right were not at all impaired on thistask.

Ž . Ž .3 Patients with a unilateral FEF lesion Fig. 13C, lefttrained to generate saccades to a remembered target posi-tion in total darkness after head and body rotation showed

Žno impairment. Similar tests after DMFC lesions Fig..13C, right revealed that patients undershot the location of

Fig. 12. Size and location of DMFC or FEF lesions in humans. Shown isa diagrammatic horizontal slice through the top portion of one hemi-sphere of the human cerebral cortex. To determine the location and size

Ž .of a lesion centered on the dorsomedial frontal cortex DMFC or frontalŽ .eye field FEF , the length and width of the cerebral cortex were set to

1.0. According to this scheme, the DMFC is situated between 0.5 and 0.8units along the length dimension and between 0.0 and 0.3 units along thewidth dimension; the FEF is situated between 0.5 and 0.75 units along thelength dimension and between 0.5 and 0.9 units along the width dimen-sion. In Figs. 13 and 14, this measuring scheme was used to determinethe borders and location of lesions confined to the FEF and DMFC of

Ž .various studies. The prefrontal cortex PFC , superior frontal sulcusŽ . Ž . Ž .SFs , precentral sulcus PCs , central sulcus Cs , and intraparietal sulcusŽ .IPs are indicated.

the remembered target position for targets appearing bothin the hemifield ipsilateral and contralateral to the lesion.

Ž . Ž4 One patient with a unilateral FEF lesion Fig. 13D,.left showed deficits in making successive saccades to two

remembered target positions in total darkness; on 20% oftrials, saccades were executed in the wrong order. Anotherpatient with a DMFC lesion tested in a similar mannershowed error rates of less than 10%; this performance was

Ž w xcomparable to that of normal control subjects Ref. 73 ,.case 1 .

Ž . Ž .5 Three of five DMFC patients Fig. 13D, right testedon a three-target task failed to successfully generate sac-cades to the remembered target positions in the same orderthe targets were presented. These three patients were testedbetween 26 and 54 days following the lesion. Two of thefive patients, tested between 38 and 84 days, did notexhibit any deficits.

Ž . Ž .6 Patients with unilateral FEF Fig. 13E, left orŽ .DMFC Fig. 13E, right lesion trained to generate ‘‘anti-

saccades’’ that forced them to shift their gaze into thehemifield opposite to where the target had appeared, per-formed on the task as well as did normal subjects. How-ever, in patients with infarcts that included the prefrontalcortex, a significant deficit was observed on this taskw x207 .


Fig. 13. DMFC or FEF lesions in humans performing oculomotor tasks.Shown are horizontal slices through the cerebral cortex. Within eachslice, the grey area represents the size and location of many lesions

Ž .combined from different patients. A Left plate shows lesions confinedw x Ž .to the FEF of 19 patients from Braun et al. 24 cases 1 to 6 ,

w x Ž . w xPierrot-Deseilligny et al. 207 cases 1 to 10 , and Rivaud et al. 213Ž .cases 1 to 3 . Right plate shows lesions confined to the DMFC of 13

w x Ž . w x Žpatients from Braun et al. 24 cases 13 to 15 , Gaymard et al. 73 cases. w x Ž . Ž .1 , and Pierrot-Deseilligny et al. 207 cases 1 to 9 . B Left plate shows

lesions confined to the FEF of eight patients from Pierrot-Deseilligny etw x Ž . w x Ž .al. 205 cases 1 to 5 and Rivaud et al. 213 cases 1 to 3 . Right plate

shows lesions confined to the DMFC of seven patients from Gaymard etw x Ž . w x Žal. 74 cases 1, 3, 4, and 5 and Pierrot-Deseilligny et al. 206 cases 1

. Ž .to 3, with right-sided lesion . C Left plate shows lesions confined to thew x Ž .FEF of five patients from Pierrot-Deseilligny et al. 205 cases 1 to 5 .

Right plate shows lesions confined to the DMFC of three patients ofw x Ž . Ž .Pierrot-Deseilligny et al. 205 cases 1 to 3 . D Left plate shows lesions

w x Žconfined to the FEF of one patient from Rivaud et al. 213 case not.specified . Right plate shows lesions confined to the DMFC of five

w x Ž . w x Žpatients from Gaymard et al. 73 case 1 and Gaymard et al. 74 cases. Ž .1, 3, 4, and 5 . E Left plate shows lesions confined to the FEF of 13

w x Ž .patients from Pierrot-Deseilligny et al. 207 cases 1 to 10 and Rivaud etw x Ž .al. 213 cases 1 to 3 . Right plate shows lesions confined to the DMFC

w x Ž .of 10 patients from Gaymard et al. 73 case 1 and Pierrot-Deseilligny etw x Ž . Ž .al. 207 cases 1 to 9 . F The plate shows lesions confined to the FEF

w x Ž .of six patients from Morrow et al. 170 cases 1 to 3 and Rivaud et al.w x Ž .213 cases 1 to 3 . See Fig. 12 for other details.

Ž . Ž .7 Patients with unilateral FEF lesions Fig. 13F testedon smooth pursuit were all impaired for ipsilaterally di-rected motion relative to the lesion but not for contralater-ally directed motion.

4.4.2. Deficits on forelimb moÕement tasksFew studies have looked at the effect of DMFC or FEF

damage on the execution of forelimb movements in pa-Ž w x. w xtients e.g., Refs. 94,293 . Viallet et al. 293 trained

Ž .patients with DMFC lesions Fig. 14A on a bimanualforelimb movement task. At the onset of a tone burst,patients were required to remove a weight from the fore-limb contralateral to the lesion with the other hand. Nor-

mally, under such conditions after the hand releases theload, the forelimb exhibits a slight flexion response. Aftera DMFC patient’s hand released the load, a larger flexionresponse than normal was observed, suggesting that theDMFC in humans is involved in bimanual postural adjust-ments.

w xHalsband and Freund 94 trained patients with frontallobe damage on a task wherein a particular visual stimulushad to be associated with a specific forelimb movement.At the onset of a stimulus, a patient was required to

Žproduce a correct movement e.g., after stimulus onset, apatient had to put the right hand on the right shoulder

.unfolding it through about 908 downward . Of the patientsŽ .studied, two had lesions confined to the DMFC Fig. 14B

Ž .and one had a lesion confined to the FEF Fig. 14C . Allthe patients had a deficit in learning the association taskbut had no difficulty imitating forelimb movements byvisual example or from memory; nor did they have prob-lems in evoking visually guided reaching movements to-ward different positions in visual space.

4.5. Summary

The nature of deficits induced by ablation of the DMFCand FEF is quite different both in kind and in magnitude.After DMFC lesions, deficits are common both in limb andeye movement control with the latter quite mild, whereasafter FEF lesions, there are no deficits in limb movementsbut impairment in some aspects of eye-movement controlare sizeable and long-lasting. Such sizeable and long-last-ing deficits following FEF ablation have been observed forthe selection of two simultaneously presented targets, forthe execution of sequences of eye movements to succes-sive targets, and for eye movements made to briefly pre-sented stimuli. DMFC lesions produced only mild deficitson these tasks that recovered within a few months. Lesionsof the posterior bank and fundus of the arcuate, but not ofthe DMFC, produce deficits in pursuit eye movements.The impairment observed in limb movements after DMFClesions is most pronounced when a bimanual task is em-ployed. The deficits documented in the FEF and DMFC

Fig. 14. DMFC or FEF lesions in humans performing skeletomotor tasks.Shown are horizontal slices through the cerebral cortex. Within eachslice, the grey area represents the size and location of many lesions

Ž .combined from different patients. A Lesions confined to the DMFC ofw x Ž . Ž .four patients from Viallet et al. 293 cases 1, 3, 4, and 5 . B Lesions

w xconfined to the DMFC of two patients from Halsband and Freund 94Ž . Ž .cases 1 and 9 . C Lesion confined to the FEF of one patient from

w x Ž .Halsband and Freund 94 case 5 . See Fig. 12 for other details.


upon reversible inactivation are similar to those found withlesions. Human studies for the most part are consistentwith the findings reported in monkeys: lesions of the FEFor DMFC do not disrupt visually guided saccades; lesionsof the FEF, but not the DMFC, impair saccades made toone remembered target position; lesions of the FEF orDMFC affect saccades generated to two or more remem-bered target positions; lesions of the FEF interfere withsmooth pursuit eye movements; and finally, lesions of theDMFC disrupt bimanual movements.

5. Single-cell recordings in the DMFC and FEF

5.1. The characteristics of single neurons in the DMFC

5.1.1. Eye and forelimb moÕementsAccumulating evidence suggests that neurons through-

out the full extent of the DMFC are modulated by forelimbŽ .movements Fig. 15A . Limb movements that are associ-

ated with neuronal activity include the displacement of amanipulandum, reaching toward and pressing buttons, andwrist extension or flexion. Unfortunately, many studiesexamining limb movements have not recorded and studiedthe eye movements that are an integral part of coordinated

w xlimb movements. Since Schlag and Schlag-Rey 242 haveŽshown that the anterior DMFC anterior to the posterior tip

.of the arcuate contains neurons that respond in associationwith eye movements, it is possible that the neuronal re-sponses interpreted to occur with limb movements may be,at least in part, due to eye movements or the combined

Ž .action involved in hand–eye coordination Fig. 15B .Cells that respond in association with eye movements

typically have been shown to be located in anterior DMFC,but a few studies have found such cells further back, inregions a few millimeters caudal to the posterior tip of the

Ž .arcuate Fig. 15B . Some studies have measured both eyeand forelimb movements while recording from the DMFCw x w x18–20,156,173,228 . Of these, only Mushiake et al. 173have dissociated the contribution of eye movement fromthe contribution of forelimb movement. In this study, amonkey was trained to reach to and look at a visual target.

Ž .Units were examined under three conditions: 1 executionŽ .of eye movements in the absence of limb movements; 2

execution of limb movements in the absence of eye move-Ž .ments; and 3 execution of both movements together. Of

12 cells studied in anterior DMFC, all exhibited their bestresponse when the eyes and forelimb movements occurred

w xtogether. Chou and Schiller 37,38 used a paradigm simi-w xlar to that of Mushiake et al. 173 while recording from

hundreds of units located within the full rostrocaudalextent of the DMFC. They found that the vast majority ofcells responded under the above noted three conditions,albeit to different degrees. These findings suggest thatmost neurons in this area are not dedicated to the execu-

Ž .Fig. 15. Location of unit recording sites in monkeys. A Top view of oneside of the DMFC showing regions from which units were recorded byinvestigators who studied monkeys as they performed a forelimb move-ment task. The cerebral midline is represented by the horizontal line.

Ž .Each tick mark on this line is spaced by 1 mm. The arcuate sulcus AsŽ .and central sulcus Cs are indicated. The posterior tip of the arcuate

Ž .sulcus Pa is shown. Each oval represents the size and location of theregion from which units modulated by a given forelimb movement taskwere found. The length and width of an oval and its center were

w xdetermined using the method of Tehovnik 280 . Studies pertaining to aŽ w x. Ž .particular recording zone are listed. Also see Ref. 130 . B Top view

of one side of the DMFC showing regions from which units wererecorded by investigators who studied monkeys as they performed anoculomotor task.

tion of a single, specific motor act. These neurons may infact be involved in hand–eye coordination.

5.1.2. Eye moÕementsNeurons within the DMFC are modulated by saccadic

wand pursuit eye movements 19,101,105,139,156,223,x228,241–243 and discharge during the presentation of

w xvisual stimuli 223,228,243 . A large proportion of cellswithin the anterior DMFC also respond vigorously when

wthe animal engages in active fixation 17,19,21,139,180,x244 . Neurons at rostral sites respond best when the center

of gaze is directed toward contralateral craniotopic space,whereas neurons at caudal sites respond best when gaze is

w xdirected toward ipsilateral craniotopic space 139 . At lat-


eral sites, responses are best for upward gaze and at medialsites, for downward gaze. Recently, the rostrocaudal topo-graphic order has been alluded to by the work of Bon and

w xLucchetti 21 . Here, a monkey was required to remainfixated and to displace a lever to detect the color change ofa peripherally located visual target. Cells in rostral DMFCtended to respond to such target changes occurring incontralateral craniotopic space, whereas cells in caudalDMFC tended to respond to such changes occurring inipsilateral craniotopic space. A population of neurons inrostral DMFC also seems to be modulated differentiallyaccording to what side of an object a monkey generates an

w xeye movement 180,181 . Thus, DMFC neurons, especiallythose in anterior DMFC, discharge during saccadic eyemovements, during smooth pursuit eye movements, duringactive fixation, and during the onset of visual stimuli. Theregion contains a topographic map for the representation ofvarious gaze positions.

5.1.3. Anterior Õs. posterior DMFCConsiderable evidence has been presented suggesting

that the anterior and posterior regions of the DMFC arew xfunctionally distinct 69,161,162,173,254,274,277,279 .

w xMatsuzaka et al. 161 found that neurons in the anteriorDMFC are modulated differently from neurons in theposterior DMFC. In their experiment, monkeys faced apanel containing two switches. A light over either the leftor right switch was illuminated briefly. A visual triggerthen signalled the monkey to press the illuminated switch.Compared to cells in the anterior DMFC, cells locatedmore caudally discharged best immediately before, during,and after the execution of the forelimb movement. Incontrast, cells in anterior DMFC were more vigorouslymodulated when the light was on as well as during theperiod between the termination of the light and the onsetof the target that triggered the forelimb movement. Thatcells in anterior DMFC are more readily modulated byvisual stimuli and respond less at the time of the forelimbmovement should not be surprising, since the region con-tains many cells that discharge to the presentation of visual

w xstimuli 223,228,243 . When tactile rather than visual stim-uli were used to initiate forelimb movement, no differencewas observed in the modulation of cells in anterior and

w xposterior DMFC 220 . Thus, to reveal a difference be-tween the anterior and posterior regions of the DMFC, avisual task must be employed.

w xTanji and Shima 279 found that 54 out of 206 unitslocated in posterior DMFC were modulated by a specific

Ž .sequence of three movements push–pull–turn of a ma-nipulandum guided by visual memory. Mushiake et al.w x Ž .174 found that a small proportion of cells 21r328located throughout the DMFC was modulated by a specificsequence of button presses. With the push–pull–turn

w xparadigm of Tanji and Shima 279 , a larger proportion ofŽ .cells in anterior DMFC 64r251 , as compared to posterior

Ž .DMFC 6r385 , exhibited a diminution of responsivity

during the continued execution of a movement sequencew xunder visual guidance 254 . At this time, it is not known

whether the sequencing-specific properties of cells in pos-terior DMFC would also diminish after prolonged taskrepetition. This question arises because it has been demon-strated that cells in posterior DMFC become quite unre-

w xsponsive after overtraining on a simple key-press task 1 .One of the problems with the studies just described is

that in none of them were eye movements under continu-ous measurement. This is of concern because the pattern ofsaccadic eye movements changes when animals learn a

w xtask that requires forelimb movements 167 . Anotherproblem is that these studies have not mapped the recep-tive fields 5 or fixation fields of neurons before they weretested on any sequencing task. Issues of overtraining, eyemovement control, and visual receptive field character-istics will need to be addressed before one can fully acceptclaims that go beyond anterior DMFC having a visual bias

w xand posterior DMFC having a skeletomotor bias 161,162 .

5.2. The characteristics of single neurons in the FEF

w xIn 1968, Bizzi 14 found that neurons in the FEFrespond during fixation and during and after the executionof saccadic eye movements. Subsequently, it was shownthat cells in FEF also discharge in response to visual

wstimuli and before saccadic eye movements 15,30,x81,169,271 . Some cells in this region are also responsive

w xduring active fixation 270 . In addition, cells have beendiscovered in deeper portions of the bank of the arcuatethat are modulated during ipsilaterally directed pursuitw x154 . Finally, the FEF appears to be topographically orga-nized such that neurons in dorsomedial sites discharge bestfor large-amplitude saccades, whereas neurons in ventro-lateral sites discharge best for small-amplitude saccadesw x31 .

Identifying neurons by antidromic activation, Segravesw xand Goldberg 248 described the basic properties of FEF

cells that project to the superior colliculus. Using similarw xmethods, Segraves 247 also characterized the FEF neu-

rons that project to the pons. Both projections were foundto relay primarily saccadic and fixation-related discharges,and they rarely had only visual responses. Recently, Som-

w xmer and Wurtz 265 presented the first description of FEFneurons that may receive input from the superior collicu-lus. Some FEF neurons could be activated via synapses byelectrical stimulation in the superior colliculus, presumably

w xdriven via a tectothalamocortical route 153 . These FEFinput neurons all had visual responses, and half had pre-saccadic bursts as well. Taken together with the results of

5 w xTolias et al. 290 describes a method to map the entire receptivefield of cortical cells within the context of the behavioural paradigm, amethod that could be employed when studying sequencing behaviour invisual areas.


w xSegraves and Goldberg 248 , this provides the first evi-dence that FEF receives visual signals at its input and

Žproduces saccade commands at its output as predicted byw x.Bruce and Goldberg 30 .

w xSegraves and Park 249 determined that movement-re-lated presaccadic FEF neurons begin their discharge ap-proximately 150 ms before saccadic onset and show peakactivity approximately 13 ms before the onset of thesaccade. These neurons can have multiple phases of activ-ity: prelude activation and a burst that occurs later. Hanes

w xet al. 96 performed an analysis of activity in the FEF andDMFC to determine the onset time of neural activity. Forpresaccadic neurons in both the FEF and DMFC, the onsettime of the burst was more tightly coupled to the begin-ning of the saccade, as opposed to the time that theinstructional trigger signal was presented. On average, FEF

Ž .neurons began bursting 28 ms S.D.s3.3 ms beforesaccades. Presaccadic neurons in the DMFC, on the otherhand, started to burst earlier than FEF neurons, and they

Žshowed greater variance in burst time means135,.S.D.s6.6 ms . Also the prelude activity in the DMFC

occurred earlier and with a greater variance in onset timethan it did in the FEF.

w xLee 138 trained monkeys to generate saccades tovisual targets presented within a region of 608=408 ofvisual space. The monkeys were required to maintainfixation for 1000 ms after which they generated a saccadeto a randomly selected target position. It was found that ahigher percentage of cells in the DMFC than FEF wasmodulated during active fixation but that a higher percent-age of cells in the FEF than DMFC was modulated duringsaccade execution. Also unlike cells in the DMFC that are

wmodulated during both eye and forelimb movements 18,x37,38,156,173 , cells in the FEF are modulated exclusively

w xduring eye movements 173 .

5.3. Summary

Neuronal responses associated with eye and limb move-ments are common in the DMFC and many single cellsrespond to both, indicating that these cells do not mediatea specific motor act. Cells in anterior portions of theDMFC tend to be more responsive to visual stimuli andthe execution of saccadic eye movements whereas in pos-terior regions, cells are more responsive to limb move-ments. Cells that discharge during fixation and smoothpursuit eye movements have also been reported.

Ž .Fig. 16. Imaging studies and the DMFC and FEF. A Shown is a topview of the human cerebral cortex. The box depicts the region fromwhich studies located maximal-activity points measured with PET orfMRI while subjects executed saccadic eye movements or smooth pursuiteye movements. The approximate location of the DMFC and FEF is

Ž .represented by the ellipses. The central sulcus Cs , precentral sulcusŽ . Ž . Ž .PCs , and superior frontal sulcus SFs are indicated. B The graphshows the location of maximal-activity points in Brodmann’s area 6observed with PET or fMRI while human subjects performed tasksinvolving the generation of saccadic or smooth pursuit eye movements.Each dot within the figure represents a maximal-activity point plotted in

w xTalairach and Tournoux 273 coordinates along the caudorostral andmediolateral axes. A dot is based on an average from 5 to 12 subjects.The subtraction method was used to determine a maximal-activity point.Typically, the baseline behaviour used for the subtraction method wasfixation of a visual target, or resting with eyes open or closed. Data were

w xobtained from the following studies: Anderson et al. 4 , Doricchi et al.w x w x w x w x55 , Kawashima et al. 119 , Luna et al. 148 , O’Driscoll et al. 178 ,

w x w x w xPaus et al. 191,192 , Petit et al. 197,198 , and Sweeney et al. 272 . Theellipses represent the distribution of maximal-activity points along thecaudorostral and mediolateral axes. The DMFC and FEF were divided

w x w x Ž .according Paus 189 and Roland and Zilles 219 . C The graph showsthe location of maximal-activity points in the DMFC of Brodmann’s area6 while human subjects performed forelimb movement tasks that did notengage the eyes. Movements could involve displacement of the shoulder,elbow, hand, or fingers or some combination of each. A dot is based onan average of 6–16 subjects. Typically, the baseline behaviour used forthe subtraction method was the total immobility of the body; often thisimmobility was conducted in total darkness with the eyes closed. Data

w xwere obtained from the following studies: Colebatch et al. 41 , Deiber etw x w x w x w xal. 51 , Dettmers et al. 53 , Jahanshahi et al. 111 , Jenkins et al. 112 ,

w x w x w xJueptner et al. 115,116 , Paus et al. 192 , Playford et al. 209 , Schlaugw x w x w xet al. 245 , Stephan et al. 269 , and van Mier et al. 292 . The ellipse

represents the distribution of maximal-activity points along the caudoros-tral and mediolateral axes. Activation in the FEF ellipse is presumablyfrom the arm area of the motor and premotor cortical areas. See B for

Ž .other details. D The graph shows the location of maximal-activity pointsin the DMFC of Brodmann’s area 6 while humans subjects performedforelimb movement tasks that engaged the eyes. The movements couldinvolve a key press, pointing movements, or movements of a manipulan-dum whose displacement was represented visually on a monitor. A dot isbased on an average of 6–24 subjects. Typically, the baseline behaviourused for the subtraction method was fixation of a visual target. Data were

w xobtained from the following studies: Corbetta et al. 42 , Grafton et al.w x w x w x w x87–90 , Kawashima et al. 117,118 , Paus et al. 192 , Sakai et al. 224 ,

w xand Sergent et al. 250 . The ellipse represents the distribution of maxi-mal-activity points along the caudorostral and mediolateral axes. See Bfor other details.


In the FEF, neurons have not been found that respondspecifically to skeletal movement. Several populations ofcells have been discerned: some have visual receptivefields, some discharge before, during and after saccadiceye movements, and some respond in association withfixation as well as smooth pursuit eye movements. Thesaccade-associated responses of many cells are tightlytime-locked to saccade execution, suggesting that thesecells contribute centrally to the initiation of eye move-ments.

For both the DMFC and FEF, recording studies supportthe topographic layout of saccadic eye movements asrevealed by electrical stimulation.

6. Event-related potentials in humans

When human subjects make self-initiated finger or handmovements, a DC shift in cortical potential can be recordedfrom scalp electrodes placed over the frontal lobes prior tothese movements. This potential was first termed‘‘bereitschaftpotential’’, or ‘‘readiness potential’’ by Ko-

w xrnhuber and Deecke 127 . It emanates primarily fromŽrostromedial recording locations in the frontal lobe elec-

Ž .troencephalogram EEG electrode locations Cz, C3, and.C4 and is evident as a slow increase in surface negativity

before self-initiated movements.The readiness potential has been divided into different

w xphases 50,252 . The first component is associated with aslow bilateral buildup of negativity. This buildup generally

occurs up to 1–2 s before the initiation of a voluntarymovement as measured by the onset of EMG activity, andis most prominent over the midline. Approximately 400 msprior to EMG onset, the negative potential increases inslope and becomes more pronounced in the hemisphere

w xcontralateral to the hand being used 49 . This marks thesecond component.

Based on differences in the location of their maxima,the two components were posited to emanate from differ-

w xent cortical areas 49 . Since the first component was mostprominent over the vertex, and was bilaterally distributed,it was proposed that its source was bilateral activation ofthe DMFC. The second component was centered morecaudally and contralateral to the hand being used. Thiscorresponded roughly with the hand region of motor cor-tex. Thus, it was proposed that the second component hasits source primarily in contralateral motor cortex.

This hypothesis of bilateral DMFC activation followedby contralateral primary motor cortex activity was consis-tent with single-unit recording evidence showing thatDMFC, but not motor cortex, was organized bilaterallyw x278 , and that it was activated earlier than was motor

w xcortex 2,276 .The DMFC motor cortex hypothesis was challenged in

humans, however, by the failure to localize the earlycomponent to the DMFC. Modeling the overall potentialby fitting different possible dipole sources, some studiesdid not find a stable solution with DMFC as the exclusive

w xsource of the early component 22 . An alternate hypothe-sis was formulated that attributed both components to the

Fig. 17. Eye movements vs. forelimb movements and DMFC activity. The frequency of maximal-activity points for a given location in the DMFC alongŽ . Ž . Ž . Ž .the caudorostral A , mediolateral B , and ventrodorsal C axes is shown for imaging experiments that studied eye movements Eye and forelimb

Ž .movements Limb . The data for the eye movement and forelimb movement studies are based on the data in Fig. 16B and C, respectively. Values alongw xeach ordinate are expressed in Talairach and Tournoux 273 coordinates. Statistical tests were conducted to determine whether the center of the eye field

differed from the center of the forelimb field. Along the caudorostral axis, the center of the eye field was anterior to the center of the forelimb fieldŽ Ž . . Ž Ž .t 27 s3.2, p-0.01 ; along the mediolateral axis, the center of the eye field was not different from the center of the forelimb field t 27 s0.006,

. Ž Ž . .p)0.05 ; along the ventrodorsal axis, the center of the eye field was ventral to the center of the forelimb field t 27 s3.1, p-0.01 . See Fig. 16 forother details.


motor cortex, with early bilateral activation followed byexclusively contralateral activation. Other studies usingdifferent recording techniques have also failed to observeconsistent early activation of the DMFC. For example,

w xNeshige et al. 176 found a clear signal in motor cortexjust prior to movement, but found only weak evidence forearly DMFC activity using subdural electrodes in epilepticpatients. Researchers have also failed to observe the readi-ness potential over the DMFC using magnetoencephalogra-

Ž .phy MEG . Countering these claims is a report by Cheynew xand Weinberg 36 , who suggested that these negative

findings were a product of the recording technique ofMEG; they proposed instead that symmetric bilateral acti-vation of both DMFCs would lead to mutually canceling

w xdipoles. Lang et al. 134 tested this hypothesis by record-ing from a patient with a unilateral DMFC lesion andfound that a dipole was indeed consistently localized overthe intact DMFC.

Several studies have shown activation of DMFC as wellas motor cortex during self-paced movements using PETw x155,218 but the poor temporal resolution of this tech-nique does not make it possible to distinguish betweenearly and late components of activation. Thus, the evi-dence is mixed regarding the role of the DMFC in thegeneration of the readiness potential.

If the DMFC is the source of the readiness potential, thepotential should be modulated by tasks that involve theDMFC to various degrees. Functions that have been at-

Fig. 18. Eye movements vs. eye and forelimb movements and DMFCactivity. The frequency of maximal-activity points for a given location inthe DMFC along the caudorostral axis is shown for the imaging experi-

Ž .ments that studied limb movements Limb and limb and eye movementsŽ .Limb and Eye . The data for Limb and Limb and Eye are based on thedata in Fig. 16C and D, respectively. Values along each ordinate are

w xexpressed in Talairach and Tournoux 273 coordinates. A statistical testwas conducted to determine whether the center of the eye and forelimbfield differed from the center of the forelimb field. Along the caudorostralaxis, the center of the eye and forelimb field was anterior to the center of

Ž Ž . .the forelimb field t 27 s3.5, p-0.01 . See Fig. 16 for other details.

Fig. 19. Simple vs. complex tasks and DMFC activity. The frequency ofmaximal-activity points for a given location in the DMFC along therostrocaudal axis is shown for the imaging experiments that studied eye

Ž . Ž .movements Eye and forelimb movements Limb , sorted according toŽ . Ž .whether the movements were simple simple or complex complex . The

data for Eye and Limb are based on the data in Fig. 16B and C,respectively. For the eye movement experiments, simple movementsincluded self-paced saccades, visually guided saccades, or visually guidedpursuit, and complex movements included memory-guided saccades,

Žanti-saccades, or conditional saccades e.g., visual objectrsaccade direc-.tion associations or gornogo saccade tasks . For the forelimb movement

experiments, simple movements included tactile- or auditory-triggeredfinger, hand, or shoulder movements, movements of a joy stick, orself-paced forelimb movements, and complex movements included anti-

Žfinger flexion movements e.g., to move the finger next to the one.stimulated , sequential movements of the fingers or joy stick, or condi-

Žtional forelimb movements e.g., to move a particular finger according to.the auditory tone delivered . Only data from experiments in which subject

were over trained are included. Values along each ordinate are expressedw xin Talairach and Tournoux 273 coordinates. Statistical tests were con-

ducted to determine whether the center of the eye and forelimb fieldsdiffered depending on whether the task performed was simple or com-plex. The center of the eye field for simple and complex tasks did not

Ž Ž . .differ t 9 s1.3, p)0.05 . Also, the center of the forelimb field forŽ Ž . .simple and complex tasks did not differ t 15 s1.64, p)0.05 . See Fig.

16 for other details.

tributed to the DMFC are sequencing of multiple move-ments and also the learning of motor tasks. The magnitudeof the readiness potential does seem to reflect the complex-ity of the task being performed and is greater prior tosequences of movements as opposed to single movementsw x48 . As previously discussed, one class of movements thatthe DMFC is thought to be specialized for is bimanual

w xcoordination. Lang et al. 136 showed that the magnitudeof the readiness potential was not only greater whensubjects performed a bimanual coordination task as com-pared to a unimanual one but it was also modulated by thedifficulty of the task. They recorded from trained musi-cians performing both an easy and a difficult bimanualrhythm and found that the readiness potential had a greatermagnitude when subjects performed the difficult task.


Fig. 20. Eye movements vs. forelimb movements and FEF activity. The frequency of maximal-activity points for a given location in the FEF along theŽ . Ž . Ž . Ž .rostrocaudal A , mediolateral B , and ventrodorsal C axes is shown for imaging experiments that studied eye movements Eye and forelimb

Ž .movements Limb . The data for the eye movement and forelimb movement studies are based on the data in Fig. 16B and C, respectively. Values alongw xeach ordinate are expressed in Talairach and Tournoux 273 coordinates. Statistical tests were conducted to determine whether the center of the eye field

differed from the center of the forelimb field. Along the caudorostral axis, the center of the eye field was anterior to the center of the forelimb fieldŽ Ž . . Ž Ž . .t 30 s2.6, p-0.01 ; along the mediolateral axis, the center of the eye field was lateral to the center of the forelimb field t 30 s4.3, p-0.01 ; along

Ž Ž . .the ventrodorsal axis, the center of the eye field was ventral to the center of the forelimb field t 30 s4.9, p-0.01 . See Fig. 16 for other details.

The readiness potential is also modulated during motorlearning. Several studies have observed a change in themagnitude of the readiness potential over the course oflearning of a difficult motor task, such as mirror tracingw x48,135,177 .

Although the majority of studies examining the readi-ness potential have used hand or finger movements, areadiness potential can also be seen prior to saccadic eye

w x w xmovements 9,57,126 and speech 91 . These findingssuggest that the readiness potential is a generalized pre-movement signal. Because of the low spatial resolution ofEEG recording, it is not known whether the pre-movementsignals all emanate from one source, or from severalsources close to each other. The readiness potential ob-served before arm, eye, foot or mouth movements couldactually be emanating from each of the respective repre-sentations in the topography known to exist in the DMFC.Experiments using finer resolution techniques, such asMEG or subdural recording, will be required to resolvethis question.

In monkeys, correlates of the readiness potential havebeen observed using a variety of techniques. Field poten-tial recordings revealed a slow potential prior to move-

w xments 97 , particularly during learning of new movementsw x75,225 . At the single-cell level, many studies have ob-served a preponderance of neurons in DMFC that dis-charge in advance of movement. Such discharge before

w xarm movements has been termed ‘‘preparatory set’’ 2,179 .Early pre-movement activity has also been observed prior

wto saccadic and smooth pursuit eye movements 105,

Ž .Fig. 21. Effects of learning on DMFC and FEF activity. A Shown is atop view of the human cerebral cortex. The approximate location of the

Ž .DMFC and FEF is represented by the ellipses. The central sulcus Cs ,Ž . Ž .precentral sulcus PCs , and superior frontal sulcus SFs are indicated.

Ž .B The graph shows the location of maximal-activity points in Brod-mann’s area 6 observed with PET or fMRI while human subjects learned

Ž . Ž . Ž .eye movement e , limb movement l , or eye and limb movement e & ltasks. Each symbol within the figure represents the location of a maxi-

w xmal-activity point plotted in Talairach and Tournoux 273 coordinates. Amaximal activity point is based on the average of 6–12 subjects. Thesubtraction method was used to determine a maximal-activity point.Typically, the baseline behaviour used for the subtraction method was theperformance of a task that resembled the learned task in terms of thetypes of movements executed except that there was no change in perfor-mance over trials. Data were obtained from the following studies: for eye

Ž . w xmovements experiments e : Kawashima et al. 119 ; for limb movementŽ . w x w xexperiments l : Jenkins et al. 112 ; Jueptner et al. 115,116 ; for eye and

Ž . w xlimb movement experiments e and l : Grafton et al. 88,89 ; Sakai et al.w x224 . The vertically oriented ellipse represents the approximate locationof the DMFC and the horizontally oriented ellipse represents the approxi-mate location of the FEF. See Fig. 16 for other details.


x228,243 . It remains to be seen whether such activity istruly analogous with human readiness potentials, and if itis modulated by the same factors.

In conclusion, the readiness potential has been observedover the DMFC of both humans and monkeys. There issome question as to whether the DMFC is the true sourceof this potential. The magnitude of this potential is affectedby motor learning, task difficulty, and whether the task isbimanual or unimanual. The readiness potential has beenstudied mainly using forelimb-movement tasks, and to alesser degree, oculomotor tasks. The somatotopic map

described for the DMFC has yet to be verified using EEGrecordings.

7. Metabolic imaging of the DMFC and FEF in humans

PET and fMRI have been used on humans to measurethe metabolic activity of the cortex as subjects performedeye and forelimb movement tasks. The metabolic activityis assumed to reflect neuronal activity. A large region of

Ž .Fig. 22. Monkey and ape frontal lobe functional maps. All panels show lateral views, with anterior to the left and dorsal at the top. A Schematic ofw xmonkey frontal lobe and the movements elicited by stimulation from each region 11 . Note that eye movements are represented in the curve of the arcuate

Ž . w xsulcus, but eyelid blinking is represented caudally, in the motor strip. B Photograph of the orangutan brain studied by Beevor and Horsley 11 ; thestippling they used to show functional areas has been modified to hatched areas for clarity. FEF, frontal eye field; EBF, eyelid blinking field; MSEF, motor

Ž . w xstrip eye field. C A representative chimpanzee brain, modified from a figure by Leyton and Sherrington 144 . In this particular animal, the MSEF wasŽ . w xnot found, but the general location of this region in other chimpanzees is indicated. D A representative gorilla brain 144 . Sites from both hemispheres

pooled together. In panels C and D, eye rotation was the primary movement evoked at sites 373 and 376; eyelid closing was the primary movement evokedŽ .from sites c, p, m, and n; and eye rotation occasionally accompanied the movements head turnings that were primarily evoked from sites N and III.


Brodmann’s area 6 becomes active when subjects generateŽ .saccadic or smooth pursuit eye movements Fig. 16A . The

medial portion of this region is presumed to be the DMFC,Žand the lateral portion is presumed to be the FEF Fig. 16B

w x.189,219 . Here, we review imaging studies and comparethe locations of the center of activation for eye movementtasks and forelimb movement tasks.

In the DMFC of monkeys, the eye field overlaps withŽ .the forelimb field see Fig. 15 . Fig. 16B, C, and D show

the distributions of maximal activity points obtained fromimaging studies conducted on the DMFC of humans asthey performed eye movements alone, or forelimb move-ments alone, or eye and forelimb movement together. The

Ž .distributions Fig. 16B and C suggest that the eye andforelimb fields of the human DMFC are overlapped. De-spite this overlap, the center of the eye field in the DMFCwas situated anterior to the center of the forelimb fieldŽ .Fig. 17A . This result is consistent with the somatotopy ofthe DMFC of monkeys, and is also consistent with earlier

w xobservations made in humans 64 . Furthermore, the centerof the DMFC’s eye field was ventral to the center of

Ž .forelimb field Fig. 17C . This is due to the fact that thesurface of the frontal lobes in humans curves downward asone advances rostrally. Finally, there was no difference inthe location of the center of the eye field in the DMFC ascompared with the center of the forelimb field along the

Ž .mediolateral dimension Fig. 17B .In most studies so far, comparisons have been based on

experiments that studied either eye movements with noforelimb involvement or forelimb movements with no eyeinvolvement. When comparisons were made between thecenter of a field based on forelimb movements that en-gaged the eyes and the center of a field based on forelimbmovements that did not engage the eyes, it was found thatthe center of the former, the limb and eye case, was

Žanterior to the center of the latter, the limb-only case Fig..18 . This indicates that by engaging the eyes during a

forelimb movement task, the center of the activity fieldwithin the DMFC shifts rostrally.

w xA recent review by Picard and Strick 204 have sug-gested that the performance of complex tasks activatesanterior regions of the DMFC and that the performance ofsimple tasks activates more posterior regions of the DMFCw x204 . We compared the centers of activity within theDMFC for simple and complex tasks that involved the

Žeyes only and forelimbs only see caption of Fig. 19 for.details . For both behaviours, there was no tendency for

the performance of complex tasks to activate regions ante-rior to those activated for the performance of simple tasks;if anything, the center of activity was situated somewhatmore caudally during the performance of complex tasksŽ .Fig. 19 . Only experiments in which subjects were over-trained on the task were considered here, since studieshave shown that learning a new task greatly augments theactivity of the DMFC when compared to the overtrained

w xcondition 224 .

Maximal activity points for the eye and forelimb fieldsŽof the human FEF region were compared Fig. 16B and C,

. 6FEF . It was found that forelimb tasks activated morecaudal and medial locations of the FEF region, whereaseye movement tasks activated more rostral and lateral

Ž .regions Fig. 20A and B . Consistent with this was theobservation that the forelimb tasks activated more dorsalsites in the cortex and the eye movement tasks activated

Ž .more ventral sites Fig. 20C . This can be explained by thefact that the surface of the frontal lobes in humans curvesdownward moving rostrally and laterally.

To summarize, the eye and forelimb fields of the humanDMFC are highly overlapped, with the center of the eyefield being somewhat more anterior to the center of theforelimb field. For comparison, the eye field within theFEF region is also situated more anterior to the forelimbfield of this region, although the forelimb field here repre-sents the forelimb area of the premotor and motor cortices.Contrary to the findings of Picard and Strick, we do notfind evidence for the idea that the anterior DMFC mediates‘‘complex’’ tasks and that the posterior DMFC mediates‘‘simple’’ tasks. When forelimb movements are accompa-nied by eye movements, the center of the activity fieldwithin the DMFC shifts rostrally. This concurs with thegeneral topographic order of human as well as monkeyDMFC.

8. Motor learning and the DMFC and FEF

Imaging experiments performed on human subjects havedisclosed that the DMFC becomes very active during the

Ž wlearning of new tasks Fig. 21 88,89,112,115,116,119,x.224 . Learning tasks that engage both the eyes and limbs

tend to similarly activate anterior and posterior sites of thew xDMFC 88,89,224 . One study has been done on the

learning of an eye movement task, and in this case, thew xanterior DMFC was activated 119 . As for the FEF, one

site only has been identified that is maximally activeduring the learning of an eye or forelimb movement task.This difference between the DMFC and FEF is quiterevealing given that in all these studies, neuronal activitywas assessed over both the DMFC and FEF.

w xSakai et al. 224 found that once human subjectsmaster the performance of a task, the activity of the DMFCdrops. They trained subjects to depress a set of buttons in aparticular order using visual guidance. The DMFC wasmore active during the performance of an underlearnedtask as compared to the performance of an overlearnedtask. Also, the readiness potential that has been attributedto the DMFC was found to exhibit a decrease in amplitude

w xonce human subjects were overtrained 133,177 .

6 Limb-related activation in the FEF region presumably is due toneurons of the primary motor cortex and premotor cortex, which abutshuman FEF.


w xChen and Wise 33,34 found that cells in the DMFC ofmonkeys were more readily modulated during the learningof an object–saccade association task than were cells inthe FEF. For this task, a monkey was required to fixate aspot where an object stimulus was subsequently presented.Following the dousing of the object stimulus and fixationspot, the monkey was required to generate a saccade to oneof four identical targets. Making a saccade to one of thefour targets produced a reward. Through trial and error, theanimal had to determine which of four saccade directionsŽ .i.e., up, down, left, or right yielded a reward for a givenobject stimulus. Neurons in the DMFC, as compared withneurons in the FEF, more often changed their firing ratewith changes in the performance of the object–saccadeassociation task.

w xAizawa et al. 1 found that training a monkey for 1year to press two keys in response to a visual targetresulted in fewer DMFC units than normal being modu-lated by the task. Only two units of 1120 tested weremodulated after 1 year of training, compared with thenormal rate of 40% observed after 1–4 months of trainingw x278 . Also more cells in the DMFC of monkeys aremodulated during the performance of a new task than

w xduring the performance of an overlearned task 175 . Asmentioned previously, once monkeys are overtrained on atask, inactivation of the DMFC is no longer disruptivew x168,227 .

Any area of the brain that participates in the learning ofmotor tasks, as the DMFC seems to, should be influencedby reward delivery given that it is usually reward thatmotivates subjects to learn. Cells in the DMFC are modu-lated while monkeys fixate different positions in cran-iotopic space for a juice reward, but not when monkeys

w xlook about freely and obtain no reward 19,139 . Mann etw xal. 156 observed that cells in the DMFC respond to the

delivery of juice only when the juice is delivered as areward for task execution but not when delivered outside

Ž .of task execution e.g., as during the intertrial interval .Also while monkeys learned an object–saccade associationtask for juice reward, many cells within the DMFC weremodulated immediately before and after the reward period.

w xOf the seven cells illustrated by Chen and Wise 33showing changes in responsivity with changes in taskperformance, five cells showed clear changes in modula-tion during the reward period.

That the DMFC has access to a reward signal shouldnot be surprising given that the substantia nigra of mon-keys sends a rich dopaminergic projection to this cortical

w xarea 12,13,63,72,143,210 , an input that is more robustthan that to the FEFrprefrontal region and other cortical

w x wareas 13,71,143 . Like the DMFC 1,33,34,133,175,177,x224 , the substantia nigra is maximally active during the

w xearly stages of learning a motor task 145,246 .In short, the DMFC seems more involved in motor

learning than the FEF. This conclusion is based on imag-ing data from humans and on single-unit recording data

from monkeys. It is apparent that the activity of the DMFCdrops with protracted training on a variety of motor tasks.After such training, lesions of the DMFC are no longerdisruptive. The DMFC has a substantial dopaminergicinput that might mediate motor learning.

9. Misplaced human FEF?

PET and fMRI studies have found that the human FEFis in the precentral sulcus, abutting or lying within theprimary motor strip. These results differ from the locationof the FEF in monkeys. The key to reconciling thisdifference may lie in a consideration of behavioural meth-ods used by imaging investigators, who assume that theirimages reflect neuronal activity related to moving the eyes.To obtain these images, data derived during control scansŽ .i.e., while subjects fixate or are at rest are subtractedfrom data derived during saccadic test scans. 7 This isintended to localize brain areas related to moving the eyes,because this is the only movement that supposedly differ-entiates the test scans from the control scans. However,another action has been well-documented to occur with

w xsaccades: eyelid blinking 58,62,298,303 . Unless subjectsare specifically instructed to inhibit blinking, it is commonfor blinking to occur when saccades are made. In contrast,subjects blink less frequently during steady fixation orduring rest. Subjects rarely blink during task-related sac-

Ž .cades those made toward a visual target, for instance butthey compensate by blinking with high likelihood during

w x‘‘return’’ saccades in the intertrial interval 58,62,303 .Blinking is particularly common for saccades greater than

w x108 in amplitude 303 , which means that blinking mayhave frequently accompanied saccades during test scans in

Ž w xsix of the eight PET studies reviewed recently Paus 189 :w x.Refs. 4,64,137,178,191,199 , in four out of the five pub-

Ž w xlished fMRI studies Refs. 43,47,171,197 ; the exceptionw x. 133is Luna et al. 148 , and even in the original Xe

regional cerebral blood flow study that started the era ofw xFEF imaging 164 . No oculomotor imaging study, to our

knowledge, has mentioned instructing the subjects not toblink, nor has any used control scans in which subjectsblinked at similar rates as detected during test scans.Accordingly, most imaging studies have probably mislo-cated the FEF caudally, toward the motor strip which

Žcontains a region that mediates blinking responses an.eyelid blinking field as well as another region that medi-

7 w xRecently 43 , the method of fMRI has made it possible to compareŽdata from different epochs of a task with each other ‘‘epoch 1’’

.image–‘‘epoch 2’’ image . The problems discussed in this section arestill relevant.


Ž .ates eye movements in humans a motor strip eye fieldŽ . 8Fig. 22 and Fig. 23A–C .

Only a single imaging study that examined saccadegeneration failed to find the FEF near the expected precen-

w xtral sulcus location 119 . In this study by Kawashima etal., subjects made a series of seven successive saccades tovisual targets, each saccadic period lasting a second, andthen subjects rested for a second, on average. The saccadeswere of relatively short amplitude 9 and nearly all saccadeswere task-related, such that blinking was probably inhib-ited until the intertrial period, when ‘‘return’’ saccades

w xwere allowed 58,62,303 . This intertrial period only oc-curred for about 1 s out of approximately every 9 s. Itwould seem that blinking once every 9 s or so is about therate expected to occur during fixation, as well. Therefore,

8 Electrical stimulation of the FEF region in monkeys causes conjugateŽ w x. Ž .eye movements e.g., Refs. 10,59,294 Fig. 22A . Eyelid blinking is

Ževoked from the face area of the precentral motor strip of monkey Fig.w x. w x22A 262 . Beevor and Horsely 11 stimulated the brain of an orangutan

Ž .and found that conjugate eye movements with no eyelid movementswere evoked from a region anterior to, and well-separated from, the

Ž .motor strip ‘‘FEF’’ in Fig. 22B . Eyelid blinking was evoked from theŽface area in the motor strip ‘‘EBF’’, for eyelid blinking field, in Fig.

.22B . A complex combination of head rotation, eye movement, andeyelid opening was also evoked within the motor strip itself, just medial

Ž .to the blinking area ‘‘MSEF’’, for motor strip eye field, in Fig. 22B .w xLeyton and Sherrington 144 confirmed all these findings in their subse-

Ž . Žquent study of orangutans, chimpanzees Fig. 22C , and gorillas Fig..22D .

When neurosurgeons began stimulating the human brain, they found thatthe oculomotor layout of humans was similar to that of anthropoid apes.

w xRasmussen and Penfield 212 evoked eye movements from 48 stimula-tion sites in 31 patients and separated their eye movement sites into two

Ž .groups. A posterior group consisted of 18 sites 37.5% of the total on theŽ .lip of the central sulcus Fig. 23A . Here, contraversive and as well as

ipsiversive movements were often evoked. An anterior group consisted ofŽ .30 sites 62.5% of the total that were mostly rostral to the precentral

Ž .sulcus Fig. 23A . At these anterior sites, nearly all the evoked move-ments were contraversive. Comparing the two groups of eye movement

Ž .sites with data from monkey and ape cf. Fig. 22 , it seems that theanterior group represents the FEF and that the posterior group representsthe motor strip eye field. Rasmussen and Penfield also evoked eyelidmovements from 27 sites in 18 patients. In contrast to the distribution of

Ž .eye movement sites, the majority of eyelid sites 63% of the total wereŽ .on the lip of the central sulcus Fig. 23B .

In order to summarize these results, we calculated the average locationsof Rasmussen and Penfield’s anterior eye field, posterior eye field, and

Ž .eyelid field, depicting each field with an ellipse Fig. 23C . The ellipsesw xwere constructed by scanning the original figures 212 into a computer

graphics program, finding the x – y location of each point, and drawingan ellipse to represent each field where the ellipse’s center was at themean x – y location and the radii of the ellipses in the x and y directionequaled the standard deviations of the points in each direction. Ras-

Ž .mussen and Penfield’s anterior eye field FEF is almost completelyŽrostral to the precentral sulcus and mostly within the middle frontal

w x.gyrus 193 . Note that this location is in excellent agreement with theŽ .location of Foerster’s FEF Fig. 1C . In contrast to the FEF, the eyelid

field and posterior eye field are mostly within the motor strip.9 Mean 15"S.D. 58, range 78–258; calculated from their Fig. 1.

we suspect that blinking activations may have been can-w xceled out in the study of Kawashima et al. 119 when

Ž .control scans fixation were subtracted from the test scans.w xKawashima et al. 119 found that, although precentral

sulcus activation was not significant, activation in theŽmiddle frontal gyrus was strong and bilateral see their

.Tables 1 and 3 . The location of this activation zone inTalairach space was xs36.5"5.3, ys25.8"12.3, andzs29.3"7.7. 10 Could this be within the true human

w xFEF? Its location in the middle frontal gyrus 119 puts itŽ .within granular cortex Fig. 23D and within the mediodor-

Ž .sal thalamus-recipient zone regio frontalis, Fig. 23E ,making it anatomically homologous to the monkey FEFŽ .see Section 2.2.1 . The location of this putative FEF inTalairach space is about 3.5 cm anterior to the precentralsulcus and thus is well-removed from the primary motorstrip. Furthermore, it is not within the dorsolateral pre-frontal cortex as mapped by imaging investigators; rather,it lies about 1.1 cm posterior to it. 11 This makes theputative human FEF location, as found by Kawashima et

w xal. 119 , homologous with monkey FEF in terms of grossw xlocation 70 . The idea, that human FEF is in the middle

frontal gyrus, has very recently been supported using amethod independent of functional imaging: transcranial

Žmagnetic stimulation combined with structural MRI Fig.w x.23D,E; Ro et al. 215 .

Thus, human imaging studies are needed that explicitlycontrol eyelid blinking so as to determine whether thehuman FEF is indeed located within the middle frontalgyrus. The oculomotor deficits that occur after damage tothe precentral region in humans might in fact be due todamage of axons originating from the middle frontal gyrus.

Ž 8.Finally, based on our analysis see , a third eye fieldmight exist in the frontal lobe of monkeys, a motor-stripeye field, immediately adjacent to the face area within theprecentral sulcus. In human imaging studies, this eye fieldmay also contribute to biasing the FEF activity fieldcaudally toward the motor cortex as subjects performoculomotor tasks.

10 Mean and standard deviations of their middle frontal gyrus activa-tions, ns4. Note, left and right hemispheres combined, so absolute valueof x was used.

11 Significantly different from the activity focus of prefrontal corteximaging, ps0.038, Mann–Whitney rank sum test, from the dorsolateralprefrontal cortex mean location of xs35.5"5.3, ys37.1"5.7, zs23.7"7.4 in Talairach coordinates; found by pooling 39 estimates ofdorsolateral prefrontal cortex that were imaged during tasks that primarily

Žinvolved working memory; right and left hemispheres combined absolute.value of x used ; values used only if authors indicate that the activation

included at least part of Brodmann’s area 46. Studies used: Cohen et al.w x w x w x w x39,40 ; Courtney et al. 44,45 ; Goldberg et al. 83 ; Haxby et al. 98 ;

w x w x w xMcCarthy et al. 163 ; Owen et al. 182–185 ; Petrides et al. 200,201 ;w xSmith et al. 260,261 .


10. Discussion

This review makes it evident that the organization andthe functions of the DMFC and FEF for the most part arequite different. In what follows, we shall discuss the

similarities and the differences that have been establishedbetween these two structures.

Ž .1 The first difference between these structures is inthe kinds of coding operations they perform. There is nowcompelling evidence to the effect that the FEF carries a


retinocentric code whereas the DMFC carries a craniocen-tric one. Two major lines of evidence support the existence

Ž .of a retinocentric code in the FEF. a Electrical stimula-tion of the area evokes predominantly contraversive sac-cades of a specific size and direction irrespective of start-

w xing eye position 216 ; there is topographic order in thelayout within the FEF for different direction and amplitude

Ž .saccadic eye movements. b Neurons in the FEF are tunedfor specific directions and sizes of saccades made into

w xcontralateral space 31 ; this arrangement corresponds withwhat has been reported with electrical stimulation. Sup-portive, if less compelling, is the evidence from lesionstudies that show deficits in saccade execution associated

w xwith the execution of vectors 54,213,263 .Two major lines of evidence support the claim that the

Ž .DMFC carries a craniocentric code. a Electrical stimula-tion of the DMFC at most sites drives the eyes to aparticular orbital position and these orbital positions are

w x Ž .topographically ordered in the DMFC 282 . b The re-sponse characteristics of single cells confirm this observa-

w xtion 139 . Lesion studies, again less compelling, are alsoin support of a craniocentric code in the DMFC; deficitshave been reported in both monkeys and humans for theexecution of saccades to two or more remembered target

w xpositions 73,74,264 ; the deficit has been attributed to afailure to store the second or subsequent target positions in

w xcraniotopic coordinates 208 .Ž .2 The second distinction between the two eye-move-

ment areas in the frontal lobe is that the DMFC is lessdedicated to the execution of saccadic eye movements thanis the FEF. The DMFC contains a representation of theentire body; stimulation evokes oculomotor as well as

Ž w x.skeletomotor responses e.g., Mitz and Wise 166 ; and

many individual neurons in the DMFC respond both to eyeand limb movements, which is not the case for FEF

w xneurons 37,38,173 .Ž .3 The third difference between these two structures is

revealed by the deficits that arise after ablation or re-versible inactivation. Inactivation or lesions of the FEFproduce deficits in saccadic latencies and velocities, ingenerating saccades to extinguished targets, in the selec-tion of simultaneously presented targets, in the executionof sequences of saccadic eye movements to successivetargets, and in pursuit eye movements; deficits in makingsaccades to extinguished targets in the selection of simulta-neously presented targets, and in the execution of se-quences of saccades are long-lasting. In contrast, DMFCinactivation and lesions produce virtually no deficits insaccades made to a single visual target or in pursuit eyemovements; the deficits seen in initiating saccades toextinguished targets and in the execution of sequences ofsaccades are of small magnitude and recover rapidly.

In support of the FEF lesion work, physiological studieshave reported neurons involved in pursuit eye movement

w xin the FEF 154 . In conflict with the DMFC lesion work,however, is the finding that DMFC neurons are modulated

w xduring pursuit eye movements 101,105 and that stimula-w xtion of the DMFC interferes with pursuit 102–104 . It is

unclear whether this latter effect is due to direct interfer-ence with neural structures involved in the execution ofpursuit eye movements. The effects reported could be dueto interference produced by the stimulation that normallydrives the eye to a termination zone.

The DMFC and the FEF are similar in having neuronsthat alter their responses as animals and humans learn newvisuomotor tasks although such neurons are more preva-

Fig. 23. Results from intraoperative stimulation in humans, and anatomical implications of our human FEF hypothesis. Anterior is to the left in all thew x Ž .panels, and dorsal is to the top. Pictures in panels A and B were flipped in mirror image from the originals 212 so as to put anterior to the left. A Human

w xFrontal lobe eye movement sites found by Rasmussen and Penfield 212 . They distinguished two groups separated by function and location, shown here asŽ .‘‘Anterior Sites’’ which includes the sites described by arrow diagrams at top and bottom and ‘‘Posterior Sites’’. Arrows describe the directions of eye

movements evoked at each site; leftward arrowspurely contraversive movement and rightward arrowspurely ipsiversive movement. Some movementsŽ .have a vertical component as well, and some are purely vertical. Also, converging arrowssconvergence and ?smovement not described. B Frontal

w x Ž . Ž .lobe eyelid movement sites found by Rasmussen and Penfield 212 . C Summary of the general locations of the FEF, the eyelid blinking field EBF , andŽ . w x Ž 8 . Ž .the motor strip eye field MSEF , according to the data of Rasmussen and Penfield 212 see for details of constructing the ellipses . D Basic

Ž .cytoarchitecture of human frontal lobe, above, compared with monkey, below. Region 2 horizontal lines is the extent of granular frontal cortex, andŽ Ž ..caudal to that but anterior to the central sulcus CS is agranular frontal cortex. The region within the bold-outlined polygon is the general predicted

Ž . Ž .location of the human FEF, lying in the middle frontal gyrus where neocortex changes from granular layer IV rostrally to agranular caudally . A similarŽ .transition is seen in monkey FEF, lying in the bank of the arcuate sulcus AS where granular cortex changes to agranular cortex. Figures derived from

w x Ž .Walker 301 . E Known connections of the human brain with respect to thalamus, above; compared with monkey, below. In human brain, the ‘‘regioŽ .frontalis’’ is connected primarily with the mediodorsal MD nucleus of the thalamus; the region caudal to that is connected primarily with the ventrolateral

Ž .VL thalamic nucleus. Our predicted FEF region in the middle frontal gyrus is probably at a transition point, being connected with both thalamic zones.Ž .Similarly, FEF in monkey is also at a transition point where cortex changes from being more connected with MD thalamus stippled to being more

Ž . w xconnected with VL thalamus cross-hatched . Human brain map is modified from Bailey and von Bonin 7 ; monkey brain map is modified from Walkerw x Ž . w x300 , chosen because he used similar methods retrograde degeneration as was used to derive the human map 65,165 . PCS, precentral sulcus. In both D

w x Ž .and E, the triangle shows the approximate mean location of middle frontal gyrus activation found by Kawashima et al. 119 , and the X shows theŽ w xapproximate regions in two human subjects where transcranial magnetic stimulation delayed saccades Ro et al. 215 ; plotted with reference to anatomy of

w x.Yousry et al. 312 . For explanation of other notations and area fills in panels D and E, see the original papers.


Ž w x.lent in the DMFC Fig. 21; Chen and Wise 33,34 . In theDMFC, a frequently made observation is a decrease in theresponses of neurons as proficiency is reached on a task.No such decrease has been reported so far for the FEF.Dopaminergic inputs to the DMFC are greater than thoseto the FEF. Whether this difference is functionally signifi-cant as it relates to learning is unclear.

Many outstanding issues pertaining to the functions ofthe DMFC and FEF remain to be addressed. Here we notethree. First, it is not known what the magnitude is of themodifiability of DMFC and FEF neurons. At the presenttime, most unit recordings are limited to a time span of afew hours; changes that arise in the course of long-termlearning have not been amenable to study. Second, itremains unclear as to what extent neurons in these areasplay a role in memory functions. Does the execution ofmotor acts in the absence of direct sensory input rely onneural circuits within these structures or are they relayed tothese areas from other regions? How are these structuresengaged during task performance once overtraining hasoccurred? Third, the exact nature of the neural code inthese areas needs to be clarified. While there is generalagreement to the effect that the FEF carries a retinocentriccode, the nature of the code in the DMFC is still underdebate, as both retinocentric and craniocentric coding oper-ations have been noted. Whether, in addition, other ego-

w x w xcentric codes 205 or even allocentric codes 180 areoperative in these or related areas needs to be assessed.

Acknowledgements

We would like to thank Andreas Tolias and DavidLeopold for comments on this review. This work wassupported by NEI grant EY-08502 to P.H. Schiller.

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